JP5091663B2 - Novel anthranilic acid derivative or salt thereof - Google Patents

Description

  The present invention relates to a novel anthranilic acid derivative or a salt thereof having a matrix metalloproteinase 13 (MMP-13) production inhibitory action.

  Matrix metalloproteases are a family of zinc-dependent proteases that use extracellular matrix components as substrates, and are activated after secretion by removing the propeptide. In humans, more than 20 kinds of matrix metalloproteases have been identified. From the domain structure and substrate specificity, collagenase (MMP-1, 8, 13), gelatinase (MMP-2, 9), stromalisin (MMP) -3, 10), matrilysin (MMP-7, 26), membrane-type MMP (MMP-14, 15, 16, 17, 24, 25) and others. This overexpression of matrix metalloprotease is observed in various cancer cells and is thought to be involved in its growth and metastasis. So far, anticancer agents that inhibit matrix metalloproteases have been developed (Non-patent Document 1).

  Matrix metalloprotease inhibitors have been developed as therapeutic agents for rheumatoid arthritis and osteoarthritis. Articular cartilage is formed by embedding cartilage-type proteoglycans, that is, aggrecan and hyaluronic acid, in a network structure of type II collagen specific to cartilage. Matrix metalloproteases are involved in maintaining these extracellular matrices. When the matrix metalloprotease and its endogenous inhibitor, TIMP (tissue inhibitor of metalloproteinases) are imbalanced and the matrix metalloprotease becomes excessive, cartilage and bone destruction progress. In particular, when collagen fibers are damaged, it causes progressive joint destruction as seen in rheumatoid arthritis and osteoarthritis. By inhibiting an excessive matrix metalloproteinase, it can be expected to suppress long-term progression of joint destruction in rheumatoid arthritis and osteoarthritis (Non-patent Document 2).

  In osteoarthritis, production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) α is also increased, and the extracellular matrix is destroyed. The production of matrix metalloprotease is further enhanced by degradation products of type II collagen and fibronectin, and the degradation of the matrix in the joint proceeds. When this matrix damage exceeds a certain threshold, the trait of the chondrocytes changes pathologically and joint destruction continues to progress. MMP-13 plays a central role in the degradation of this type II collagen (Non-patent Document 3).

Current Oncology Reports, Volume 6, Pages 96-102, 2004 Anals of the Rheumatic Diseases, Volume 60, 62-67, 2001 Biochemical Society Symposia, 70, 115-123, 2003

  There is a strong need for agents that inhibit matrix metalloprotease, especially MMP-13 production.

「式中、Ｒ^１は、水素原子またはカルボキシル保護基を；Ｒ^２は、水素原子またはイミノ保護基を；Ｒ^３は、置換されていてもよいフェニル基で置換されている単環の複素環式基；または下記置換基群（１）から選ばれる１つ以上の基で置換されていてもよいフェニル、シクロアルキルもしくは二環式の複素環式基を；Ｒ^４は、下記置換基群（２）および（３）から選ばれる１つ以上の基で置換されていてもよいフェニル、チエニル、シクロアルキル、シクロアルケニルもしくは二環式の複素環式基；または下記置換基群（２）および（４）から選ばれる１つ以上の基で置換されていてもよいピリジル基を；Ｘ^１は、置換されていてもよいアルキレンもしくはアルケニレン基または結合手を；Ｘ^２は、カルボニル基または一般式−Ｘ^３−Ｘ^４−、−Ｘ^４−Ｘ^３−、−Ｏ−Ｘ^４−もしくは−Ｘ^４−Ｃ（Ｏ）ＮＨ−（但し、各一般式の左側の結合手が、Ｒ^４に結合するものとする。）「式中、Ｘ^３は、硫黄原子、保護されていてもよいイミノ基、スルフィニル基、スルホニル基または結合手を；Ｘ^４は、置換されていてもよいアルキレンもしくはアルケニレン基または結合手を意味する。」で表される基を意味する。
［置換基群（１）］
ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノ基、保護されていてもよいヒドロキシル基、置換されていてもよいアルキル基、置換されていてもよいアルケニル基、置換されていてもよいアルキニル基、置換されていてもよいアルコキシ基、置換されていてもよいアリール基、置換されていてもよい環状アミノ基、置換されていてもよいアルアルキル基または置換されていてもよい複素環式基
［置換基群（２）］
ハロゲン原子、シアノ基、ニトロ基、アミノ基、環状アミノ基、低級アルキルアミノ基、カルボキシル基、ヒドロキシル基、低級アルキル基、アルコキシ基およびアリール基から選ばれる１つ以上の基で置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルまたは複素環式基
［置換基群（３）］
ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノ基または保護されていてもよいヒドロキシル基
［置換基群（４）］
シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノ基または保護されていてもよいヒドロキシル基
」で表されるアントラニル酸誘導体またはその塩が、ＭＭＰ−１３産生阻害作用を有することを見出し、本発明を完成させた。Under such circumstances, the present inventors conducted extensive studies, and as a result, the general formula [1]

“Wherein R ¹ represents a hydrogen atom or a carboxyl protecting group; R ² represents a hydrogen atom or an imino protecting group; R ³ represents a monocyclic heterocyclic ring substituted with an optionally substituted phenyl group Or a phenyl, cycloalkyl or bicyclic heterocyclic group optionally substituted with one or more groups selected from the following substituent group (1); R ⁴ represents the following substituent group ( 2) and phenyl, thienyl, cycloalkyl, cycloalkenyl or bicyclic heterocyclic group which may be substituted with one or more groups selected from (3); or the following substituent groups (2) and ( 4) a pyridyl group optionally substituted with one or more groups selected from: X ¹ represents an optionally substituted alkylene or alkenylene group or a bond; X ² represents a carbonyl group or a general formula- X ^{3 X 4 -, - X 4 -X} 3 -, - O-X 4 - or ^-X 4 -C (O) NH- (where the bond on the left side of each general formula, and those that bind to ^{R 4} "In the formula, X ³ represents a sulfur atom, an optionally protected imino group, a sulfinyl group, a sulfonyl group or a bond; X ⁴ represents an optionally substituted alkylene or alkenylene group or a bond. Means a group represented by.
[Substituent group (1)]
Halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamide group, carbamoyl group, sulfamoyl group, lower alkylamino group, amino group which may be protected, optionally protected A hydroxyl group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, a substituted An optionally substituted cyclic amino group, an optionally substituted aralkyl group or an optionally substituted heterocyclic group [substituent group (2)]
It may be substituted with one or more groups selected from a halogen atom, cyano group, nitro group, amino group, cyclic amino group, lower alkylamino group, carboxyl group, hydroxyl group, lower alkyl group, alkoxy group and aryl group Good alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl or heterocyclic group [substituent group (3)]
Halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamido group, carbamoyl group, sulfamoyl group, lower alkylamino group, optionally protected amino group or optionally protected Hydroxyl group [Substituent group (4)]
Cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamide group, carbamoyl group, sulfamoyl group, lower alkylamino group, amino group which may be protected or hydroxyl group which may be protected. '' Was found to have an MMP-13 production inhibitory action, and the present invention was completed.

  The novel anthranilic acid derivative or salt thereof of the present invention has an MMP-13 production inhibitory action and is useful as a therapeutic agent for diseases involving MMP-13 such as rheumatoid arthritis, osteoarthritis and cancer.

Hereinafter, the compound of the present invention will be described in detail.
In the present specification, unless otherwise specified, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, Linear or branched C _1-12 alkyl groups such as isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl; lower alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, Linear or branched C _1-6 alkyl groups such as butyl, sec-butyl, isobutyl, tert-butyl, pentyl and isopentyl; an alkenyl group is, for example, vinyl, allyl, propenyl, isopropenyl, Butenyl, isobutenyl, pentenyl, hexenyl, hepteni And a linear or branched C _2-12 alkenyl group such as octenyl; Alkynyl groups, for example, ethynyl, 2-propynyl and 2-linear butynyl or branched-chain C _{2 A -12} alkynyl group; a cycloalkyl group is a C _3-8 cycloalkyl group such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; a cycloalkenyl group is, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclo A C _3-8 cycloalkenyl group such as hexenyl;

An alkylene group is, for example, a linear or branched C _1-6 alkylene group such as methylene, ethylene, propylene, butylene and hexylene; an alkenylene group is, for example, vinylene, propenylene, 1-butenylene and A linear or branched C _2-6 alkenylene group such as 2-butenylene; an aryl group such as phenyl and naphthyl; an aralkyl group such as benzyl, diphenylmethyl, AlC _1-6 alkyl groups such as trityl, phenethyl and naphthylmethyl; alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and isopentyl Linear or minute, such as oxy The chain C _1-6 alkyloxy group; and alkoxyalkyl groups, for example, a C _1-6 alkyloxy C _1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl; and an aralkyloxyalkyl group For example, an ar C _1-6 alkyloxy C _1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl;

Examples of the acyl group include linear or branched C _2-12 alkanoyl groups such as formyl group, acetyl, propionyl and isovaleryl, al C _1-6 alkylcarbonyl groups such as benzylcarbonyl, benzoyl and naphthoyl. Cyclic hydrocarbon carbonyl groups, nicotinoyl, thenoyl, heterocyclic carbonyl groups such as pyrrolidinocarbonyl and furoyl, succinyl group, glutaryl group, maleoyl group, phthaloyl group and amino acids (amino acids include, for example, glycine, alanine, valine) , Leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, . The tryptophan, proline and the like hydroxyproline and the like) from the induced N-terminus may be protected linear or branched and α- amino alkanoyl group;

The alkyloxycarbonyl group is, for example, linear or branched such as methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-pentyloxycarbonyl. A branched C _1-12 alkyloxycarbonyl group; an aralkyloxycarbonyl group is, for example, an al C _1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups; an aryloxycarbonyl group; For example, a group such as phenyloxycarbonyl;

An acyloxy group is, for example, a linear or branched C _2-6 alkanoyloxy group such as acetyloxy and propionyloxy, and an aroyloxy group such as benzoyloxy; an acylalkyl group is, for example, acetylmethyl, Groups such as benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methoxybenzoylmethyl and 1-benzoylethyl; acyloxyalkyl groups include, for example, acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl Groups such as;

An arylthio group is, for example, a group such as phenylthio; an alkanesulfonyl group is, for example, a C _1-6 alkanesulfonyl group such as methanesulfonyl, ethanesulfonyl, and propanesulfonyl; an arylsulfonyl group is, for example, benzenesulfonyl A group such as toluenesulfonyl and naphthalenesulfonyl; an alkylthioalkyl group is, for example, a C _1-6 alkylthio C _1-6 alkyl group such as methylthiomethyl, ethylthiomethyl and propylthiomethyl; an arylthioalkyl group A group such as phenylsulfenylmethyl and 2- (p-nitrophenylsulfenyl) ethyl; an alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy The arylsulfonyloxy group, for example, a benzenesulfonyloxy and toluenesulfonyloxy groups, such as oxy;; C _1-6 alkanesulfonyloxy a sulfonyloxy group and an arylsulfonyl group is, for example, a group such as p- toluenesulfonyl ethyl; An alkanesulfonamide group is, for example, a C _1-6 alkanesulfonamide group such as methanesulfonamide and ethanesulfonamide;

Monocyclic heterocyclic groups include, for example, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl and pyrazolidinyl groups Monocyclic nitrogen-containing heterocyclic groups containing only nitrogen atoms as hetero atoms forming a ring; furyl, pyranyl, tetrahydropyranyl, 1,3-dioxolyl, 1,3-dioxanyl, 1,4-dioxanyl group, etc. A monocyclic oxygen-containing heterocyclic group containing only an oxygen atom as a heteroatom forming the ring; a monocyclic sulfur-containing heterocycle containing only a sulfur atom as a heteroatom forming the ring, such as a thienyl group Formula group: oxazolyl, oxadiazolyl, isoxazo A monocyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring such as ru and morpholinyl groups; forming the rings such as thiazolyl, isothiazolyl, thiadiazolyl and thiomorpholinyl groups Monocyclic nitrogen-containing / sulfur heterocyclic groups containing only nitrogen and sulfur atoms as the hetero atoms; and monocyclic containing only oxygen atoms and sulfur atoms as the hetero atoms forming the ring, such as thioxanyl groups. Oxygen and sulfur heterocyclic groups;

Bicyclic heterocyclic groups include, for example, indolyl, indolinyl, isoindolyl, indolizinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinolidinyl, isoquinolyl, phthalazinyl, Two of the condensed or bridged rings containing only a nitrogen atom as a hetero atom forming the ring, such as naphthyridinyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, quinuclidinyl and 2,3-dihydrobenzopyrrolyl groups Cyclic nitrogen-containing heterocyclic groups; such rings as benzofuranyl, isobenzofuranyl, chromenyl, isochromanyl, benzo-1,3-dioxolyl, benzo-1,4-dioxanyl and 2,3-dihydrobenzofuranyl groups Shape A bicyclic oxygen-containing heterocyclic group represented by a condensed ring or a bridged ring containing only an oxygen atom as a heteroatom, and a heteroatom forming the ring, such as a benzothienyl and a 2,3-dihydrobenzothienyl group A bicyclic sulfur-containing heterocyclic group represented by a condensed ring or a bridged ring containing only a sulfur atom as a nitrogen atom and oxygen as a hetero atom forming the ring such as a benzomorpholinyl and benzomorpholonyl group A bicyclic nitrogen-containing / oxygen heterocyclic group represented by a condensed ring or a bridged ring containing an atom; and a condensed ring or bridged ring containing a nitrogen atom and a sulfur atom as hetero atoms forming the ring, such as a benzothiazolyl group A bicyclic nitrogen-containing / sulfur heterocyclic group represented by:

The oxygen-containing heterocyclic group is, for example, a group such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; the sulfur-containing heterocyclic group is, for example, a group such as tetrahydrothiopyranyl; Examples of the group include groups such as 2-furfuryloxycarbonyl and 8-quinolyloxycarbonyl; and examples of the nitrogen-containing heterocyclic alkyl group include groups such as phthalimidomethyl and succinimidomethyl;

Heterocyclic groups include, for example, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, imidazolinyl, imidazolidinyl, pyrazolinyl and pyrazolidinyl groups. A monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a hetero atom, such as furyl, pyranyl, tetrahydropyranyl, 1,3-dioxolyl, 1,3-dioxanyl and 1,4-dioxanyl groups A monocyclic oxygen-containing heterocyclic group containing only an oxygen atom as a heteroatom forming the ring; a monocyclic sulfur-containing heterocyclic group containing only a sulfur atom as the heteroatom forming the ring, such as a thienyl group; Oxazolyl, oxadiazolyl, isoxazolyl A monocyclic nitrogen-containing / oxygen heterocyclic group containing only a nitrogen atom and an oxygen atom as a hetero atom forming the ring such as a morpholinyl group; a hetero ring forming a ring such as a thiazolyl, isothiazolyl, thiadiazolyl and thiomorpholinyl group Monocyclic nitrogen-containing / sulfur heterocyclic groups containing only nitrogen and sulfur atoms as term atoms; monocyclic oxygen-containing containing only oxygen atoms and sulfur atoms as heterogeneous atoms forming the ring such as thioxanyl groups Sulfur heterocyclic groups; indolyl, indolinyl, isoindolyl, indolizinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinolidinyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, dihydroquinoxa Linyl, quinazoli Bicyclic nitrogen-containing heterocyclic groups represented by condensed or bridged rings containing only nitrogen atoms as hetero atoms forming such rings such as ru, cinnolinyl, purinyl, quinuclidinyl and 2,3-dihydrobenzopyrrolyl groups Groups; heteroatoms forming the ring such as benzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, benzo-1,3-dioxolyl, benzo-1,4-dioxanyl and 2,3-dihydrobenzofuranyl groups A bicyclic oxygen-containing heterocyclic group represented by a condensed ring or a bridged ring containing only an oxygen atom as a ring; only a sulfur atom as a hetero atom forming the ring such as a benzothienyl and 2,3-dihydrobenzothienyl group A bicyclic sulfur-containing heterocyclic group represented by a condensed ring or a bridged ring containing benzoxazolyl, benzoisoxazolyl, A bicyclic nitrogen-containing / oxygen heterocyclic group represented by a condensed ring or a bridged ring containing only a nitrogen atom and an oxygen atom as heterogeneous atoms forming the ring, such as a benzomorpholinyl group and a benzomorpholonyl group; And oxygen atoms, nitrogen atoms, and the like such as bicyclic nitrogen-containing / sulfur heterocyclic groups represented by fused or bridged rings containing only nitrogen and sulfur atoms as the hetero atoms forming the ring such as benzothiazolyl groups A monocyclic, bridged or fused heterocyclic group containing at least one heteroatom selected from sulfur atoms;

The lower alkylamino group includes, for example, mono C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino and pentylamino; cyclopropylamino, cyclobutylamino and A C _3-6 cycloalkylamino group such as cyclopentylamino; and a diC _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino and dibutylamino;

The cyclic amino group may be, for example, either a saturated cyclic amino group or an unsaturated cyclic amino group, and one or more hetero atoms such as nitrogen atom, oxygen atom, sulfur atom and carbonyl in the ring. It may contain carbon, and may be monocyclic or bicyclic, and more specifically, aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, Saturated or unsaturated with one nitrogen atom such as pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, piperidin-1-yl, dihydroazepin-1-yl and perhydroazepin-1-yl A monocyclic 3- to 7-membered cyclic amino group: imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, pipette Has two nitrogen atoms such as din-1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yl and homopiperazin-1-yl Saturated or unsaturated monocyclic 3-7 membered cyclic amino group; 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1,2-dihydro-1,2 Saturated or unsaturated monocyclic 3-7 membered cyclic amino groups having 3 or more nitrogen atoms, such as 1,4-triazin-1-yl and perhydro-S-triazin-1-yl; Isoxazolidin-2-yl, morpholin-4-yl, thiazolidin-3-yl, isothiazolidin-2-yl, thiomorpholin-4-yl, homothiomorpholin-4-yl and 1,2,4 A saturated or unsaturated monocyclic 3 to 7-membered cyclic amino group having 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom in addition to a nitrogen atom such as thiadiazoline-2-yl; isoindoline-2-yl Saturated or unsaturated 2- or 3-cyclic cyclic amino groups such as, indolin-1-yl, 1H-indazol-1-yl, purin-7-yl and tetrahydroquinolin-1-yl; and 5-azaspiro [2 .4] heptane-5-yl, 2,8-diazabicyclo [4.3.0] nonan-8-yl, 3-azabicyclo [3.1.0] hexan-3-yl, 2-oxa-5,8 Spiro formulas such as diazabicyclo [4.3.0] nonan-8-yl, 2,8-diazaspiro [4.4] nonan-2-yl and 7-azabicyclo [2.2.1] heptan-7-yl Or cross-linking A saturated or unsaturated 5- to 12-membered cyclic amino group; a substituted silyl group, for example, a group such as trimethylsilyl, triethylsilyl, and tributylsilyl; an alkylsilylalkyl group, for example, 2- (trimethylsilyl) Means a group such as ethyl;

  Amino protecting groups include all groups that can be used as protecting groups for ordinary amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-615, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, acyl group, alkyloxycarbonyl group, aralkyloxycarbonyl group, aryloxycarbonyl group, aralkyl group, alkoxyalkyl group, aralkyloxyalkyl group, arylthio group, alkanesulfonyl group, arylsulfonyl group And substituted silyl groups.

  The imino protecting group includes all groups that can be used as protecting groups for ordinary imino groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-615, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specific examples include an acyl group, an alkyloxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, an aralkyl group, an alkoxyalkyl group, an arylthio group, an alkanesulfonyl group, an arylsulfonyl group, and a substituted silyl group. Can be mentioned.

  Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pp. 17-245, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, acyl group, alkyloxycarbonyl group, aralkyloxycarbonyl group, heterocyclic oxycarbonyl group, alkyl group, alkenyl group, aralkyl group, oxygen-containing heterocyclic group, sulfur-containing heterocyclic group , Alkoxyalkyl groups, aralkyloxyalkyl groups, alkanesulfonyl groups, arylsulfonyl groups, substituted silyl groups, and the like.

  The carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 369-453, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, alkyl group, alkenyl group, aryl group, aralkyl group, acylalkyl group, arylthioalkyl group, arylsulfonylalkyl group, oxygen-containing heterocyclic group, alkylsilylalkyl group, acyloxyalkyl group, Examples thereof include nitrogen-containing heterocyclic alkyl groups, cycloalkyl groups, alkoxyalkyl groups, aralkyloxyalkyl groups, alkylthioalkyl groups, and substituted silyl groups.

  The phenolic hydroxyl protecting group includes all groups that can be used as protecting groups for ordinary phenolic hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 246-287, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, acyl group, alkyl group, alkenyl group, aralkyl group, oxygen-containing heterocyclic group, sulfur-containing heterocyclic group, alkoxyalkyl group, alkanesulfonyl group, arylsulfonyl group, substituted silyl group, etc. Is mentioned.

  Examples of thiol protecting groups include all groups that can be used as protecting groups for ordinary thiol groups. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 454-493, 1999, John Wiley & Sons (John Wiley & Sons, INC.). Specific examples include an acyl group, an alkyl group, an alkenyl group, an aralkyl group, an alkoxyalkyl group, and a substituted silyl group.

  Examples of the leaving group include a halogen atom, an alkanesulfonyloxy group, an arylsulfonyloxy group, and an acyloxy group.

Examples of the salt of the compound represented by the general formula [1] include salts that are generally known in basic groups such as amino groups or acidic groups such as phenolic hydroxyl groups or carboxyl groups.
Salts in basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrogen bromide and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and Examples thereof include salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Salts with nitrogenous organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine and N, N′-dibenzylethylenediamine Is mentioned.
Furthermore, among the above salts, preferred salts of the compound of the general formula [1] include pharmacologically acceptable salts.

In the present invention, an alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic group which may be substituted on the phenyl group, cycloalkyl group or bicyclic heterocyclic group of R ^{3 in} the present invention are: It may be substituted with one or more groups selected from a halogen atom, a cyano group, a nitro group, an amino group, a cyclic amino group, a lower alkylamino group, a carboxyl group, a hydroxyl group, a lower alkyl group, an alkoxy group and an aryl group. Good.
The phenyl group substituted by the monocyclic heterocyclic group of R ^{3 in} the present invention is a halogen atom, cyano group, nitro group, amino group, cyclic amino group, lower alkylamino group, carboxyl group, hydroxyl group, lower group. It may be substituted with one or more groups selected from an alkyl group, an alkoxy group, an aryl group, and the like.

The alkylene group or alkenylene group of X ¹ and X ⁴ in the present invention is a halogen atom, a cyano group, a nitro group, an amino group, a cyclic amino group, a lower alkylamino group, a carboxyl group, a hydroxyl group, a lower alkyl group, an alkoxy group, and It may be substituted with one or more groups selected from aryl groups and the like.

In the compound of the present invention, preferred compounds include the following compounds.
A compound in which R ¹ is a hydrogen atom is preferable.
A compound in which R ² is a hydrogen atom is preferable.

R ³ is a monocyclic heterocyclic group substituted with an optionally substituted phenyl group; or a halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamide group, Carbamoyl group, sulfamoyl group, lower alkylamino group, amino group which may be protected, hydroxyl group which may be protected, alkyl group which may be substituted, alkenyl group which may be substituted, substituted An optionally substituted alkynyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted cyclic amino group, an optionally substituted aralkyl group and an optionally substituted A phenyl or bicyclic heterocyclic group optionally substituted with one or more groups selected from heterocyclic groups Compounds are preferred, monocyclic heterocyclic groups substituted with an optionally substituted phenyl group; or halogen atoms, cyano groups, hydroxyl groups, optionally substituted alkyl groups, optionally substituted A good alkenyl group, an optionally substituted alkynyl group, an optionally substituted alkoxy group, an optionally substituted aryl group, an optionally substituted cyclic amino group, an optionally substituted alkalkyl group And more preferably a compound which is a phenyl or bicyclic heterocyclic group which may be substituted with one or more groups selected from optionally substituted heterocyclic groups, and is substituted with a phenyl group Monocyclic heterocyclic group; or halogen atom, hydroxyl group, optionally substituted alkyl group, optionally substituted alkoxy group, optionally substituted More preferred is a compound which is phenyl or a bicyclic heterocyclic group which may be substituted with one or more groups selected from an aryl group and an optionally substituted heterocyclic group, and is substituted with a phenyl group A pyrazolyl, isoxazolyl, thiazolyl or thiadiazolyl group; or one or more groups selected from a halogen atom, a hydroxyl group, an alkyl group optionally substituted with a halogen atom and an alkoxy group optionally substituted with a halogen atom More preferred is a compound which is a phenyl group which may be substituted with.

A compound in which R ⁴ is phenyl or a bicyclic heterocyclic group which may be substituted with one or more groups selected from the following substituent groups (2a) and (3a) is preferred. A compound which is phenyl or a bicyclic heterocyclic group which may be substituted with one or more groups selected from (2b) and (3b) is more preferred, and an alkyl group which may be substituted with a halogen atom More preferred is a compound which is phenyl optionally substituted with one or more groups selected from an alkoxy group optionally substituted with a halogen atom, a halogen atom and a hydroxyl group.
[Substituent Group (2a)]
It may be substituted with one or more groups selected from a halogen atom, cyano group, nitro group, amino group, cyclic amino group, lower alkylamino group, carboxyl group, hydroxyl group, lower alkyl group, alkoxy group and aryl group Good alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl or heterocyclic group [substituent group (2b)]
It may be substituted with one or more groups selected from a halogen atom, cyano group, nitro group, amino group, cyclic amino group, lower alkylamino group, carboxyl group, hydroxyl group, lower alkyl group, alkoxy group and aryl group Good alkyl, alkoxy, aryl, cyclic amino or heterocyclic group [substituent group (3a)]
Halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamido group, carbamoyl group, sulfamoyl group, lower alkylamino group, optionally protected amino group or optionally protected Hydroxyl group [Substituent group (3b)]
Halogen atom, cyano group, lower alkylamino group, optionally protected amino group or optionally protected hydroxyl group

X ¹ is preferably an alkylene or alkenylene group optionally substituted with a group selected from an optionally substituted alkyl and phenyl group, or a compound having a bond, and an compound having an alkylene group, an alkenylene group or a bond is More preferably, a compound that is an alkenylene group or a bond is more preferable, and a compound that is a bond is even more preferable.

X ² is a carbonyl group, or a general formula —O—X ^4a — or —X ^4a —C (O) NH— (where the bond on the left side of each general formula is bonded to R ⁴ ). In the formula, X ^4a means an optionally substituted alkylene group or a bond ”is preferable.
X ² is represented by the general formula -X ^3a -X ^4b -or -X ^4b -X ^3a- (provided that the bond on the left side of each general formula is bonded to R ⁴ ) "wherein X ^3a Represents a sulfur atom, an optionally protected imino group or a bond; X ^4b represents an alkylene or alkenylene group or bond optionally substituted with a group selected from an optionally substituted alkyl and phenyl group. Is preferably an alkylene group, an alkenylene group or a bond, more preferably a compound which is an alkylene group or a bond.

  Among the compounds of the present invention, representative compounds include, for example, compounds described in Tables 1 to 5 below.

  In the compound of the general formula [1] or a salt thereof, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), the present invention includes those isomers, In addition, solvates, hydrates and crystals of various shapes are included.

Next, the manufacturing method of this invention compound is demonstrated.
The compound of the present invention is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.

「式中、Ｒ^１ａは、カルボキシル保護基を；Ｒ^５は、水素原子または低級アルキル基を；Ｘ^５は、置換されていてもよいアルキレン基を；Ｌ^１は、脱離基を；Ｒ^３、Ｒ^４、Ｘ^１およびＸ^４は、前記と同様の意味を示す。」[Production Method 1]

“Wherein R ^1a represents a carboxyl protecting group; R ⁵ represents a hydrogen atom or a lower alkyl group; X ⁵ represents an optionally substituted alkylene group; L ¹ represents a leaving group; R ³ , R ⁴ , X ¹ and X ⁴ have the same meaning as described above.

  Examples of the compound of the general formula [3a] include pyridine-3-boronic acid, 4- (methanesulfonamido) phenylboronic acid, thiophene-2-boronic acid, benzofuran-2-boronic acid, and 3-methoxyphenylboronic acid. It has been known. As the compound of the general formula [3b], for example, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinoline and the like are known. In addition, the compounds of the general formulas [3a] and [3b] can be produced from the corresponding halogeno isomers according to, for example, the method described in JP-A-2003-206290.

The compound of the general formula [1a] is obtained by converting the compound of the general formula [2] into the general formula [3a] or [3b] in the presence or absence of a base, in the presence of a palladium catalyst, in the presence or absence of a ligand. It can manufacture by making it react with the compound of.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; benzene , Aromatic hydrocarbons such as toluene and xylene; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; acetonitrile What nitriles, esters such as ethyl acetate and butyl acetate; and the like sulfoxides such as dimethyl sulfoxide and the like, may be used which are mixed.

  Examples of the base that is optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine, diisopropylethylamine, tributylamine and N, N-dicyclohexylmethylamine. Can be mentioned. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [2].

  Examples of the palladium catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; inorganic palladium salt such as palladium chloride; organic palladium salt such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Organopalladium complexes such as bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride and tris (dibenzylideneacetone) dipalladium (0); and polymer support Examples include polymer-fixed organic palladium complexes such as bis (acetate) triphenylphosphinepalladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphinepalladium (II). It may be used in combination. The usage-amount of a palladium catalyst is 0.00001-1 times mole with respect to the compound of General formula [2], Preferably, what is necessary is just 0.001-0.1 times mole.

  The ligands optionally used in this reaction include: trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphine such as triphenylphosphine and tritolylphosphine Trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; Imidazolium salts such as bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetylacetate Diketones such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; and 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1, 1′-binaphthyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2- (di-tert-butylphosphino) -2 ', 4', 6'-triisopropylbiphenyl, 2- (di-tert-butylphosphino) biphenyl, and the like, and these may be used in combination. The amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].

The amount of the compound of the general formula [3a] or [3b] used may be 1 to 50 times mol, preferably 1 to 3 times mol for the compound of the general formula [2].
This reaction is preferably carried out at 40 to 220 ° C. for 1 minute to 96 hours in an inert gas (for example, nitrogen, argon) atmosphere.

「式中、Ｒ^４ａは、ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよいシクロアルケニル基を；Ｒ^４ｂは、ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよいシクロアルキル基を；Ｘ^１ａは、置換されていてもよいアルキレン基または結合手を；Ｒ^１ａ、Ｒ^３、Ｘ^１およびＬ^１は、前記と同様の意味を示す。」[Production Method 2]

"In the formula, R ^4a is a halogen atom, a cyano group, a nitro group, an acyl group, an alkanesulfonyl group, an alkanesulfonamide group, an acetamido group, a carbamoyl group, a sulfamoyl group, a lower alkylamino group, an amino group that may be protected. And a hydroxyl group and a cycloalkenyl group optionally substituted with one or more groups selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic group; R ^4b is a halogen atom, a cyano group, a nitro group, an acyl group, an alkanesulfonyl group, an alkanesulfonamide group, an acetamide group, a carbamoyl group, a sulfamoyl group, a lower alkylamino group, an optionally protected amino and hydroxyl group, and Even if it is replaced There alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic least one cycloalkyl group which may be substituted with a group selected from the group; X ^1a is substituted R ^1a , R ³ , X ¹ and L ¹ have the same meaning as described above.

(2-1)
As compounds of the general formula [4], for example, cyclopentene and cyclohexene are known. The compound of the general formula [4] can be produced, for example, by the method described in Experimental Chemistry Course, 4th edition, volume 19, pages 53-298, 1992, Maruzen or a method analogous thereto. .

The compound of the general formula [1b] is represented by the general formula [2] in the presence or absence of a base, in the presence or absence of a phase transfer catalyst, in the presence or absence of a ligand, in the presence of a palladium catalyst. The compound can be produced by reacting with the compound of the general formula [4].
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; benzene , Aromatic hydrocarbons such as toluene and xylene; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; acetonitrile What nitriles, esters such as ethyl acetate and butyl acetate; and the like sulfoxides such as dimethyl sulfoxide and the like, may be used which are mixed.

  Bases optionally used in this reaction include, for example, inorganic bases such as sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, and sodium acetate, potassium acetate, sodium = tert-butoxide. And organic bases such as triethylamine, diisopropylethylamine, tributylamine and N, N-dicyclohexylmethylamine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [2].

  Examples of the phase transfer catalyst optionally used in this reaction include tetramethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate. And quaternary ammonium salts such as trioctylmethylammonium chloride; N-laurylpyridinium chloride, N-lauryl-4-picolinium chloride, N-laurylpicolinium chloride; and N-benzylpicolinium chloride. The amount of the phase transfer catalyst used may be 0.01 to 50 times mol, preferably 0.1 to 5 times mol, of the compound of the general formula [2] or a salt thereof.

  Examples of ligands that are optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri-tert-butyl-phosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triphenylphosphine and tritolylphosphine, and the like. Triarylphosphines; trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1 Imidazolium salts such as 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoro Diketones such as cetylacetone; amines such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; and 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1 , 1′-binaphthyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2- (di-tert-butylphosphino ) -2 ′, 4 ′, 6′-triisopropylbiphenyl, 2- (di-tert-butylphosphino) biphenyl, and the like, and these may be used in combination. The amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.001 to 0.1 times mol, of the compound of the general formula [2].

Examples of the palladium catalyst used in this reaction include metal palladium such as palladium-carbon and palladium black; inorganic palladium salt such as palladium chloride; organic palladium salt such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride, tris (dibenzylideneacetone) dipalladium (0) and (E) -di (μ- Organopalladium complexes such as acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II); and polymer-supported bis (acetato) triphenylphosphine palladium (II) and polymer-supported di (acetato) dicyclohexyl Le triphenylphosphine palladium (II) include such polymers immobilized organic palladium complexes such as may be used these in combination. The usage-amount of a palladium catalyst is 0.00001-1 times mole with respect to the compound of General formula [2], Preferably, what is necessary is just 0.001-0.5 times mole.
The amount of the compound of the general formula [4] used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [2].
This reaction is preferably carried out in an inert gas (for example, nitrogen, argon) atmosphere at 40 to 170 ° C. for 1 minute to 48 hours.

(2-2)
The compound of the general formula [1c] can be produced by reducing the compound of the general formula [1b].
Examples of the reduction reaction include a catalytic hydrogenation reaction using a metal catalyst.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; N Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; nitriles such as acetonitrile; acetone and 2-butano Ketones such as, esters such as ethyl acetate and butyl acetate; carboxylic acids such as acetic acid; and heteroaromatics such as well as pyridine and the like, may be used which are mixed.

Examples of the metal catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; nickel metal such as Raney nickel; and platinum salts such as platinum oxide. Can be mentioned. The amount of the metal catalyst used may be 0.001 to 1 times the amount of the compound of the general formula [1b] (W / W), preferably 0.01 to 1 times the amount (W / W).
Examples of the reducing agent include hydrogen; formic acid; formate salts such as sodium formate, ammonium formate and triethylammonium formate; and cyclohexene and cyclohexadiene. The amount of the reducing agent to be used is 2 to 100 times mol, preferably 2 to 10 times mol, of the compound of the general formula [1b].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.

「式中、Ｒ^４ｃは、ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよいフェニル、チエニル、シクロアルキルもしくは二環式の複素環式基；またはシアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよいピリジル基を；Ｘ^３ｂは、酸素原子、硫黄原子、保護されていてもよいイミノ基、スルフィニル基、スルホニル基または結合手を；Ｘ^４ｃは、置換されていてもよいアルケニレン基を；Ｘ^４ｄは、置換されていてもよいアルキレン基を；Ｒ^１ａ、Ｒ^３、Ｒ^４、Ｘ^１、Ｘ^１ａおよびＬ^１は、前記と同様の意味を示す。」[Production Method 3]

Wherein R ^4c is a halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, carbamoyl group, sulfamoyl group, lower alkylamino group, amino and hydroxyl group which may be protected. And optionally substituted phenyl, thienyl, cycloalkyl or divalent one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic groups. A cyclic heterocyclic group; or a cyano group, a nitro group, an acyl group, an alkanesulfonyl group, an alkanesulfonamide group, a carbamoyl group, a sulfamoyl group, a lower alkylamino group, an optionally protected amino and hydroxyl group, and a substituent Optionally substituted alkyl A pyridyl group optionally substituted by one or more groups selected from alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic groups; X ^3b is an oxygen atom, sulfur atom, protected X ^4c represents an optionally substituted alkenylene group; X ^4d represents an optionally substituted alkylene group; R ^1a , R ³ ; an optionally substituted imino group, sulfinyl group, sulfonyl group or bond; , R ⁴ , X ¹ , X ^1a and L ¹ have the same meaning as described above.

  As the compound of the general formula [5], for example, styrene, allylbenzene, 4-phenyl-1-butene, vinylcyclohexane and allylcyclohexane are known. The compound of the general formula [5] can be produced by, for example, the method described in Experimental Chemistry Course, 4th edition, volume 19, pages 298-361, 1992, Maruzen, or a method analogous thereto. .

(3-1)
The compound of the general formula [1d] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [5] according to the production method (2-1).

(3-2)
The compound of the general formula [1e] can be produced by reducing the compound of the general formula [1d] according to the production method (2-2).

「式中、Ｘ^２ａは、酸素原子または一般式−Ｘ^４−Ｘ^３ａ−（但し、各一般式の左側の結合手が、Ｒ^４に結合するものとする。）「式中、Ｘ^３ａおよびＸ^４は、前記と同様の意味を示す。」で表される基を；Ｒ^１ａ、Ｒ^３、Ｒ^４、Ｘ^１およびＬ^１は、前記と同様の意味を示す。」[Production Method 4]

^{"Wherein, X 2a} represents an oxygen atom or the formula ^-X 4 ^{-X 3a} - (. Which, however, bonds of the left side of each general formula, and those that bind to ^{R 4)" wherein, X 3a} and X ⁴ has the same meaning as described above. ”R ^1a , R ³ , R ⁴ , X ¹ and L ¹ have the same meaning as described above. "

  As the compound of the general formula [6], for example, aniline, benzylamine, benzenethiol, phenylmethanethiol and the like are known. Moreover, the compound of General formula [6] can be manufactured by a conventional method from a corresponding halogeno compound, for example.

(4-1)
The compound of the general formula [1f] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [6] according to the production method (2-1).

(4-2)
When X ^2a is an oxygen atom, the compound of the general formula [1f] reacts with the compound of the general formula [6] in the presence or absence of a base and in the presence of a copper catalyst. Can be manufactured.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; N, N-dimethylformamide, N, N Amides such as dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether Ketones such as acetone and 2-butanone; nitriles such as acetonitrile; esters such as ethyl acetate and butyl acetate; and ketones such as dimethyl sulfoxide; Sulfoxide such, and the like, it may be used which are mixed.

Examples of the base optionally used in this reaction include sodium hydride and sodium. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [2].
Examples of the copper catalyst used in this reaction include copper powder and copper iodide. The usage-amount of a copper catalyst is 0.00001-1 times mole with respect to the compound of General formula [2], Preferably, what is necessary is just 0.01-1 times mole.
The amount of the compound of general formula [6] used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of general formula [2].
This reaction may be carried out at 40 to 200 ° C. for 30 minutes to 72 hours.

「式中、Ｒ^４ｄは、ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよいフェニル、チエニルもしくは二環式の複素環式基；またはシアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよいピリジル基を；Ｌ^２は、脱離基を；Ｒ^１ａ、Ｒ^３、Ｘ^１およびＸ^４ｃは、前記と同様の意味を示す。」[Production Method 5]

In the formula, R ^4d is a halogen atom, a cyano group, a nitro group, an acyl group, an alkanesulfonyl group, an alkanesulfonamide group, an acetamido group, a carbamoyl group, a sulfamoyl group, a lower alkylamino group, or an amino group that may be protected. And a hydroxyl group, and optionally substituted phenyl, thienyl or di-substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic groups Cyclic heterocyclic group; or cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamide group, carbamoyl group, sulfamoyl group, lower alkylamino group, amino and hydroxyl which may be protected Group as well as substituted A pyridyl group optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic groups; L ² represents a leaving group; R ^1a , R ³ , X ¹ and X ^4c have the same meaning as described above.

  As compounds of general formula [8], for example, 2-iodotoluene, 3-iodoanisole, 1-iodo-3-nitrobenzene and 6-iodo-2,3-dihydrobenzo [1,4] dioxin are known. Yes. The compound of the general formula [8] can be produced, for example, by the method described in Experimental Chemistry Course, 4th edition, volume 19, pages 460 to 482, 1992, Maruzen or a method analogous thereto. .

  The compound of the general formula [1g] can be produced by reacting the compound of the general formula [7] with the compound of the general formula [8] according to the production method (2-1).

「式中、Ｘ^２ｂは、一般式−Ｘ^４−Ｃ（Ｏ）ＮＨ−または一般式−Ｘ^４−ＳＯ_２ＮＨ−（但し、各一般式の左側の結合手が、Ｒ^４に結合するものとする。）「式中、Ｘ^４は、前記と同様の意味を示す。」で表される基を；Ｒ^１ａ、Ｒ^３、Ｒ^４およびＸ^１は、前記と同様の意味を示す。」[Production Method 6]

“In the formula, X ^2b represents a general formula —X ⁴ —C (O) NH— or a general formula —X ⁴ —SO ₂ NH— (where the bond on the left side of each general formula is bonded to R ^4. A group represented by “in the formula, X ⁴ has the same meaning as described above”; R ^1a , R ³ , R ⁴ and X ¹ have the same meaning as described above. "

(6-1)
X ^2b is represented by the general formula —X ⁴ —C (O) NH— (where the bond on the left side of each general formula is bonded to R ⁴ ) “wherein X ⁴ is the same as described above. In the case of the group represented by “, the compound of the general formula [1h] can be produced by amidating the compound of the general formula [9]. Specific examples include a method using an acid halide in the presence or absence of a base and a method using an acid anhydride in the presence or absence of a base.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone. Amides; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether Nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and butyl acetate; sulfones such as sulfolane; It is like sulfoxides such as methyl sulfoxide, may be used which are mixed.

  Examples of the acid halide used in this reaction include benzoyl chloride, benzoyl bromide, 2,4-difluorobenzoyl chloride, diphenylacetyl chloride, 2,3-dihydrobenzo [1,4] dioxin-6-carbonyl chloride, cyclohexane. Examples include carbonyl chloride, cyclopentanecarbonyl chloride, (trans) -3-phenylacryloyl chloride, phenoxyacetyl chloride, 1-benzofuran-2-carbonyl chloride, 2-thenoyl chloride, nicotinoyl chloride, and picolinoyl chloride. The acid halide can be produced by reacting the corresponding carboxylic acid with thionyl chloride or oxalyl chloride. The amount of the acid halide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [9].

Examples of the acid anhydride used in this reaction include benzoic anhydride. Moreover, an acid anhydride can be manufactured from a corresponding carboxylic acid by, for example, a method described in New Experimental Chemistry Course, Vol. 14, pages 1120 to 1133, 1977, Maruzen, or a method analogous thereto. The amount of the acid anhydride to be used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [9].
Examples of the base optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine and diisopropylethylamine. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [9].
This reaction is usually carried out at −78 to 100 ° C., preferably 0 to 80 ° C., for 10 minutes to 24 hours.

(6-2)
X ^2b is represented by the general formula —X ⁴ —SO ₂ NH— (where the bond on the left side of each general formula is bonded to R ⁴ ) “wherein X ⁴ has the same meaning as described above. In the case of the group represented by the formula, the compound of the general formula [1h] can be produced by sulfonamidating the compound of the general formula [9]. Specifically, a method using a sulfonyl halide in the presence or absence of a base can be mentioned.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone. Amides; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic hydrocarbons such as benzene, toluene and xylene; Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether Nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and butyl acetate; sulfones such as sulfolane; It is like sulfoxides such as methyl sulfoxide, may be used which are mixed.

Examples of the sulfonyl halide used in this reaction include benzenesulfonyl chloride and α-toluenesulfonyl chloride. The sulfonyl halide can be produced from the corresponding sulfonic acid by, for example, a method described in Maruzen, New Experimental Chemistry Course, Vol. 14, pp. 1784-1792, 1978, or a method analogous thereto. The amount of the sulfonyl halide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [9].
Examples of the base optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine and diisopropylethylamine. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [9].
This reaction is usually carried out at −78 to 100 ° C., preferably 0 to 80 ° C., for 10 minutes to 24 hours.

「式中、Ｘ^３ｃは、酸素原子、硫黄原子または保護されていてもよいイミノ基を；Ｒ^１ａ、Ｒ^３、Ｒ^４、Ｘ^１、Ｘ^４ａ、Ｘ^４ｄおよびＬ^２は、前記と同様の意味を示す。但し、Ｘ^４ａが、結合手の場合、Ｒ^４は、置換されていてもよいシクロアルキル基を示す。」[Production Method 7]

“Wherein X ^3c represents an oxygen atom, a sulfur atom or an optionally protected imino group; R ^1a , R ³ , R ⁴ , X ¹ , X ^4a , X ^4d and L ² are the same as defined above. In the case where X ^4a is a bond, R ⁴ represents an optionally substituted cycloalkyl group.

  As the compound of the general formula [11a], for example, benzyl bromide and (2-bromoethyl) benzene are known. As the compound of the general formula [11b], for example, 3-phenyl-1-propanol and cyclohexanol are known.

(7-1)
The compound of the general formula [1i] can be produced by reacting the compound of the general formula [10] with the compound of the general formula [11a] in the presence of a base.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; Nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and butyl acetate; sulfones such as sulfolane; and It is like sulfoxides such as methyl sulfoxide, may be used which are mixed.

The amount of the compound of general formula [11a] used for this reaction may be 1 to 20 times mol, preferably 1 to 5 times mol, of the compound of general formula [10].
Examples of the base used in this reaction include organic amines such as dimethylaminopyridine, triethylamine and pyridine; alkali metal hydrides such as sodium hydride; and alkali metal carbonates such as potassium carbonate and sodium carbonate. . The usage-amount of a base should just be 1-20 times mole with respect to the compound of General formula [10], Preferably, it may be 1-5 times mole.
This reaction is usually carried out at 0 to 200 ° C., preferably 25 to 150 ° C. for 10 minutes to 24 hours.

(7-2)
When X ^3c is an oxygen atom or a sulfur atom, the compound of general formula [1i] is obtained by subjecting the compound of general formula [10] and the compound of general formula [11b] to Mitsunobu reaction in the presence of an azodicarbonyl compound and phosphines. It can manufacture by attaching | subjecting to.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol dimethyl ether, ethylene Ethers such as glycol monomethyl ether and ethylene glycol dimethyl ether; esters such as methyl acetate, ethyl acetate and butyl acetate; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; Examples thereof include halogenated hydrocarbons such as chloroform and methylene chloride, and these may be used in combination.

Examples of the azodicarbonyl compound used in this reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate and azodicarbonyldipiperidine. The amount of the azodicarbonyl compound used may be 1 to 5 times mol, preferably 1 to 3 times mol, of the compound of the general formula [10].
Examples of phosphines used in this reaction include triaryl phosphines such as triphenyl phosphine and trialkyl phosphines such as tributyl phosphine. The usage-amount of phosphine should just be 1-5 times mole with respect to the compound of General formula [10], Preferably, it may be 1-3 times mole.
The amount of the compound of general formula [11b] used may be 1 to 5 times mol, preferably 1 to 3 times mol, of the compound of general formula [10].
This reaction is usually performed at -20 to 120 ° C, preferably 0 to 50 ° C, for 30 minutes to 24 hours.

「式中、Ｒ^３ａは、ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよいフェニルもしくは二環式の複素環式基；または置換されていてもよいフェニル基のみで置換されている単環の複素環式基を；Ｒ^１ａ、Ｒ^４、Ｘ^２およびＬ^２は、前記と同様の意味を示す。」[Production Method 8]

“In the formula, R ^3a is a halogen atom, a cyano group, a nitro group, an acyl group, an alkanesulfonyl group, an alkanesulfonamide group, an acetamide group, a carbamoyl group, a sulfamoyl group, a lower alkylamino group, or an amino group that may be protected. And a hydroxyl group and phenyl or bicyclic optionally substituted with one or more groups selected from optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic groups Or a monocyclic heterocyclic group substituted only with an optionally substituted phenyl group; R ^1a , R ⁴ , X ² and L ² have the same meanings as described above . "

  As compounds of the general formula [13], for example, iodobenzene, 1-fluoro-4-iodobenzene, 1-iodo-3-nitrobenzene and 6-iodo-2,3-dihydrobenzo [1,4] dioxin are known. It has been.

(8-1)
The compound of the general formula [1j] is produced by, for example, the method described in Journal of American Chemical Society, Vol. 125, pages 6653-6655, 2003, etc. Can do. Specifically, in the presence or absence of a base, in the presence or absence of a phase transfer catalyst, in the presence or absence of a ligand, in the presence of a palladium catalyst, the compound of the general formula [12] is represented by the general formula It can manufacture by making it react with the compound of [13].
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; benzene , Aromatic hydrocarbons such as toluene and xylene; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; acetonitrile What nitriles, esters such as ethyl acetate and butyl acetate; and the like sulfoxides such as dimethyl sulfoxide and the like, may be used which are mixed.

  Examples of the base optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and sodium acetate, potassium acetate, sodium = tert-butoxide, triethylamine, diisopropylethylamine and tributylamine. Of the organic base. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [12].

  Examples of the phase transfer catalyst optionally used in this reaction include tetramethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium hydrogen sulfate. And quaternary ammonium salts such as trioctylmethylammonium chloride; N-laurylpyridinium chloride, N-lauryl-4-picolinium chloride, N-laurylpicolinium chloride; and N-benzylpicolinium chloride. The amount of the phase transfer catalyst used may be 0.01 to 50 times mol, preferably 0.1 to 5 times mol, of the compound of the general formula [12] or a salt thereof.

  Examples of ligands that are optionally used in this reaction include trialkylphosphines such as trimethylphosphine and tri (tert-butyl) phosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triphenylphosphine and tritolylphosphine, and the like. Triarylphosphines; trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; 1 Imidazolium salts such as 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoro Diketones such as cetylacetone; amines such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; and 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1 , 1′-binaphthyl and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and the like, and these may be used in combination. The amount of the ligand used may be 0.00001 to 1 times mol, preferably 0.001 to 0.2 times mol, of the compound of the general formula [12].

Examples of the palladium catalyst used in this reaction include metal palladium such as palladium-carbon and palladium black; inorganic palladium salt such as palladium chloride; organic palladium salt such as palladium acetate; tetrakis (triphenylphosphine) palladium (0), Organopalladium complexes such as bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride and tris (dibenzylideneacetone) dipalladium (0); and polymer support Examples include polymer-fixed organic palladium complexes such as bis (acetate) triphenylphosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II). It may be used in combination. The usage-amount of a palladium catalyst is 0.00001-1 times mole with respect to the compound of General formula [12], Preferably, what is necessary is just 0.001-0.1 times mole.
The amount of the compound of general formula [13] used may be 1 to 50 times mol, preferably 1 to 3 times mol, of the compound of general formula [12].
This reaction is preferably carried out at 40 to 170 ° C. for 1 minute to 72 hours in an inert gas (for example, nitrogen, argon) atmosphere.

(8-2)
When L ² is a chlorine atom, a bromine atom or an iodine atom, the compound of the general formula [1j] can be used in the presence or absence of a base, in the presence or absence of a ligand, It can be produced by reacting a compound of the formula [12] with a compound of the general formula [13].
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; benzene , Aromatic hydrocarbons such as toluene and xylene; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; acetonitrile What nitriles, esters such as ethyl acetate and butyl acetate; and the like sulfoxides such as dimethyl sulfoxide and the like, may be used which are mixed.

  Examples of the base that is optionally used in this reaction include inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine, diisopropylethylamine and N-methylmorpholine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [12].

Examples of ligands that are optionally used in this reaction include amino acids such as proline, N, N-dimethylglycine, and alanine. The amount of the ligand used may be 1 to 50 times mol, preferably 2 to 5 times mol, of the compound of the general formula [12].
Examples of the copper catalyst used in this reaction include copper, copper bromide and copper iodide, and these may be used in combination. The usage-amount of a copper catalyst is 0.01-50 times mole with respect to the compound of General formula [12], or its salt, Preferably, what is necessary is just 0.1-5 times mole.
The amount of the compound of general formula [13] used may be 1 to 50 times mol, preferably 1 to 2 times mol, of the compound of general formula [12].
This reaction is preferably carried out at 10 to 180 ° C. for 1 minute to 24 hours in an inert gas (for example, nitrogen, argon) atmosphere.

「式中、Ｒ^１ａ、Ｒ^３、Ｒ^４、Ｘ^１ｂ、Ｘ^２およびＬ^２は、前記と同様の意味を示す。」[Production Method 9]

“In the formula, R ^1a , R ³ , R ⁴ , X ^1b , X ² and L ² have the same meaning as described above.”

  As compounds of the general formula [14], for example, benzyl bromide and (2-bromoethyl) benzene are known.

The compound of general formula [1k] can be produced by reacting the compound of general formula [12] with the compound of general formula [14] in the presence of a base.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; Nitriles such as acetonitrile; ketones such as acetone and 2-butanone; esters such as ethyl acetate and butyl acetate; sulfones such as sulfolane; and It is like sulfoxides such as methyl sulfoxide, may be used which are mixed.
The amount of the compound of general formula [14] used in this reaction may be 1 to 5 times mol, preferably 1 to 1.5 times mol, of the compound of general formula [12].
Examples of the base used in this reaction include organic amines such as dimethylaminopyridine, triethylamine and pyridine; alkali metal hydrides such as sodium hydride and alkali metal carbonates such as potassium carbonate and sodium carbonate.
The amount of the base used may be 1 to 20 times mol, preferably 1 to 5 times mol, of the compound of the general formula [12].
This reaction is usually carried out at 0 to 200 ° C., preferably 25 to 150 ° C. for 10 minutes to 24 hours.

「式中、Ｌ^３は、脱離基を；Ｒ^１ａ、Ｒ^３、Ｒ^４、Ｘ^１およびＸ^２は、前記と同様の意味を示す。」[Production method 10]

“Wherein L ³ represents a leaving group; R ^1a , R ³ , R ⁴ , X ¹ and X ² have the same meaning as described above.

  As the compound of the general formula [16], for example, aniline, cyclohexylamine, benzylamine and the like are known.

The compound of the general formula [1l] is produced by reacting the compound of the general formula [15] with the compound of the general formula [16] according to the production method (8-1) or the production method (8-2). be able to.

「式中、Ｒ^２ａは、イミノ保護基を；Ｘ^２ｃは、酸素原子、カルボニル基または結合手を；Ｒ^３およびＲ^４は、前記と同様の意味を示す。」[Production Method 11]

“Wherein R ^2a represents an imino protecting group; X ^2c represents an oxygen atom, a carbonyl group or a bond; R ³ and R ⁴ have the same meaning as described above.

The compound of the general formula [1m] can be produced by reacting the compound of the general formula [17] with an oxidizing agent in the presence or absence of an acid or a base and in the presence or absence of a salt.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aliphatic such as hexane and cyclohexane Hydrocarbons; and pyridine, and the like. These may be used as a mixture.

Examples of the acid used as desired in this reaction include mineral acids such as sulfuric acid and nitric acid. The usage-amount of an acid should just be 1-100 times mole with respect to the compound of General formula [17].
Examples of the base that is optionally used in this reaction include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as pyridine. The usage-amount of a base should just be 1-100 times mole with respect to the compound of general formula [17].
Examples of the salt that is optionally used in this reaction include magnesium sulfate, ammonium sulfate, and magnesium chloride. The amount of the salt used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [17].
Examples of oxidizing agents used in this reaction include chromate salts such as chromium (VI) oxide and sodium dichromate, and peroxygen salts such as potassium permanganate, barium permanganate, calcium permanganate and magnesium permanganate. Manganates are mentioned. The amount of the oxidizing agent used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [17].
This reaction is usually carried out at 0 to 150 ° C., preferably 40 to 130 ° C., for 30 minutes to 48 hours.

「式中、Ｘ^１ｂは、置換されていてもよいアルキレンまたはアルケニレン基を；Ｒ^２、Ｒ^３ａ、Ｒ^４、Ｘ^２およびＬ^２は、前記と同様の意味を示す。」[Production method 12]

“Wherein, X ^1b represents an alkylene or alkenylene group which may be substituted; R ² , R ^3a , R ⁴ , X ² and L ² have the same meaning as described above.

  As the compound of the general formula [19], for example, benzyl bromide and (2-bromoethyl) benzene are known.

The compound of the general formula [1n] can be produced by reacting the compound of the general formula [18] with the compound of the general formula [19] according to the production method (7-1).

「式中、Ｒ^３、Ｒ^４、Ｘ^１、Ｘ^２およびＬ^３は、前記と同様の意味を示す。」[Production method 13]

“Wherein R ³ , R ⁴ , X ¹ , X ² and L ³ have the same meaning as described above.”

The compound of the general formula [1o] is produced by reacting the compound of the general formula [20] with the compound of the general formula [16] according to the production method (8-1) or the production method (8-2). be able to.

「式中、Ｒ^２ａ、Ｒ^３、Ｒ^４、Ｘ^１およびＸ^２は、前記と同様の意味を示す。」[Production Method 14]

“In the formula, R ^2a , R ³ , R ⁴ , X ¹ and X ² have the same meaning as described above.”

The compound of the general formula [1o] is, for example, W.W. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-615, 1999, John Wiley & Sons (John Wiley & Sons, INC.) Can be produced by deprotecting the compound represented by the general formula [1p].
Examples of the deprotection reaction include a hydrolysis reaction using an acid or a base, a dealkylation reaction using a salt, a reductive dealkylation reaction including a metal catalyst hydrogenation reaction, and a hydrazine decomposition reaction.

(14-1)
In the hydrolysis reaction using an acid, examples of the acid used include formic acid, hydrochloric acid, sulfuric acid, hydrogen bromide, trifluoroacetic acid, aluminum chloride, and trimethylsilane iodide. The amount of the acid used may be 1 to 10000 times mol, preferably 1 to 5000 times mol, of the compound of the general formula [1p].
In the hydrolysis reaction using a base, examples of the base used include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate; sodium methoxide, sodium ethoxide and potassium tert- And organic bases such as butoxide; and tetrabutylammonium fluoride. The amount of the base used may be 1 to 1000 times mol, preferably 1 to 50 times mol, of the compound of the general formula [1p].
In the dealkylation reaction using a salt, examples of the salt used include lithium iodide and sodium chloride. The amount of the salt used may be 1 to 100 times mol, preferably 1 to 10 times mol, of the compound of the general formula [1p].
The reductive dealkylation reaction including the metal catalyst hydrogenation reaction may be performed according to the production method (2-2).

The solvent used in these reactions is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; nitriles such as acetonitrile; aliphatic hydrocarbons such as hexane and cyclohexane Aromatic hydrocarbons such as benzene, toluene and xylene; sulfoxides such as dimethyl sulfoxide; N, N-dimethylformamide and the like Amides; nitromethane; and pyridine and the like, it may be used which are mixed.
This reaction is usually carried out at −78 to 130 ° C., preferably 0 to 120 ° C., for 10 minutes to 24 hours.

(14-2)
In the hydrazine decomposition reaction, the amount of hydrazine to be used may be 1 to 1000 times mol, preferably 1 to 100 times mol, of the compound of general formula [1p].
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; dioxane Ethers such as tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; nitriles such as acetonitrile; aliphatic hydrocarbons such as hexane and cyclohexane Aromatic hydrocarbons such as benzene, toluene and xylene; sulfoxides such as dimethyl sulfoxide; a, such as N, N-dimethylformamide; Earth; nitromethane; and pyridine and the like, it may be used which are mixed.
This reaction is usually carried out at −78 to 170 ° C., preferably 0 to 130 ° C., for 10 minutes to 24 hours.

「式中、Ｒ^３、Ｒ^４、Ｘ^１およびＸ^１ａは、前記と同様の意味を示す。」[Production Method 15]

“Wherein R ³ , R ⁴ , X ¹ and X ^1a have the same meaning as described above.”

  The compound of the general formula [1r] can be produced by reducing the compound of the general formula [1q] according to the production method (2-2).

「式中、Ｒ^３、Ｒ^４、Ｒ^４ｃ、Ｘ^１、Ｘ^１ａ、Ｘ^４ｃおよびＸ^４ｄは、前記と同様の意味を示す。」[Production Method 16]

“Wherein R ³ , R ⁴ , R ^4c , X ¹ , X ^1a , X ^4c and X ^4d have the same meaning as described above.

  The compound of the general formula [1t] can be produced by reducing the compound of the general formula [1s] according to the production method (2-2).

「式中、Ｒ^１ａ、Ｒ^３、Ｒ^４、Ｘ^１およびＸ^２は、前記と同様の意味を示す。」[Production Method 17]

“In the formula, R ^1a , R ³ , R ⁴ , X ¹ and X ² have the same meaning as described above.”

  The compound of the general formula [1o] can be produced by deprotecting the compound of the general formula [1l] according to the production method (14-1).

「式中、Ｘ^３ｄは、スルフィニル基またはスルホニル基を；Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ^１およびＸ^４は、前記と同様の意味を示す。」[Production Method 18]

“Wherein X ^3d represents a sulfinyl group or a sulfonyl group; R ¹ , R ² , R ³ , R ⁴ , X ¹ and X ⁴ have the same meaning as described above.

The compound of the general formula [1v] can be produced by oxidizing the compound of the general formula [1u].
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aliphatic such as hexane and cyclohexane Hydrocarbons; and pyridine, and the like. These may be used as a mixture.
Examples of the oxidizing agent used in this reaction include hydrogen peroxide; peracids such as peracetic acid, perbenzoic acid and m-chloroperbenzoic acid; peroxides such as tert-butyl peroxide; and sodium metaperiodate. Is mentioned. The amount of the oxidizing agent used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [1u].
This reaction is usually performed at 0 to 150 ° C., preferably 10 to 100 ° C., for 30 minutes to 48 hours.

「式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ^１、Ｘ^３ｄおよびＸ^４は、前記と同様の意味を示す。」[Production Method 19]

“Wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ^3d and X ⁴ have the same meaning as described above.

  The compound of the general formula [1x] can be produced by oxidizing the compound of the general formula [1w] according to the production method 18.

「式中、Ｌ^４は、塩素原子、臭素原子またはヨウ素原子を；Ｒ^１ａ、Ｒ^３、Ｒ^４ｄ、Ｘ^１およびＸ^５は、前記と同様の意味を示す。」[Production Method 20]

“In the formula, L ⁴ represents a chlorine atom, a bromine atom or an iodine atom; R ^1a , R ³ , R ^4d , X ¹ and X ⁵ have the same meaning as described above.”

  As compounds of the general formula [41], for example, 2-iodotoluene, 3-iodoanisole, 3-iodonitrobenzene and 6-iodo-2,3-dihydrobenzo [1,4] dioxin are known.

  The compound of the general formula [1y] can be produced by reacting the compound of the general formula [40] with the compound of the general formula [41] according to the production method 1.

「Ｒ^４ｅは、ハロゲン原子、シアノ基、ニトロ基、アシル基、アルカンスルホニル基、アルカンスルホンアミド基、アセトアミド基、カルバモイル基、スルファモイル基、低級アルキルアミノ基、保護されていてもよいアミノおよびヒドロキシル基ならびに置換されていてもよいアルキル、アルケニル、アルキニル、アルコキシ、アリール、環状アミノ、アルアルキルおよび複素環式基から選ばれる１つ以上の基で置換されていてもよい、該環を形成する窒素原子を介して結合する二環式の複素環式基を；Ｒ^１ａ、Ｒ^３、Ｘ^１およびＬ^１は、前記と同様の意味を示す。」[Production method 21]

“R ^4e is a halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamide group, carbamoyl group, sulfamoyl group, lower alkylamino group, amino or hydroxyl group which may be protected. And a nitrogen atom forming the ring, which may be substituted with one or more groups selected from an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl and heterocyclic group A bicyclic heterocyclic group bonded via a group; R ^1a , R ³ , X ¹ and L ¹ have the same meaning as described above.

  As the compound of the general formula [42], for example, indoline, benzimidazole, indole and the like are known.

  The compound of the general formula [1z] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [42] according to the production method (8-1).

The general formulas [1a], [1b], [1c], [1d], [1e], [1f], [1g], [1h], [1i], [1j], [1j], [1k], [1l], [1m], [1n], [1o], [1p], [1q], [1r], [1s], [1t], [1u], [1v], [1w] , [1x], [1y] and [1z] or salts thereof are subjected to a reaction known per se, such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis. Or by appropriately combining these reactions, it can be derived into other compounds of the general formula [1] or salts thereof.
Moreover, in the compound in the above production method, when there are isomers (for example, optical isomers, geometric isomers, tautomers, etc.), these isomers can also be used, and solvates. Hydrates and crystals of various shapes can also be used.

  Next, the general formulas [2], [7], [9], [10], [12], [15], [17], [18], [20] and A method for producing the compound of [40] will be described.

「式中、Ｒ^１ａ、Ｒ^３、Ｒ^３ａ、Ｒ^５、Ｘ^１、Ｘ^５、Ｌ^１およびＬ^２は、前記と同様の意味を示す。」[Production method A]

“Wherein R ^1a , R ³ , R ^3a , R ⁵ , X ¹ , X ⁵ , L ¹ and L ² have the same meanings as described above.

  For example, 4-bromo-2-nitrobenzoic acid is known as a compound of the general formula [21].

(A-1)
The compound of the general formula [22] can be produced by esterifying the compound of the general formula [21]. This reaction is W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 369-453, 1999, John Wiley and Sons (John Wiley) & Sons, INC.) Or a method analogous thereto. Specific examples include a method using an alkylating agent in the presence or absence of a phase transfer catalyst and a base and a method via an acid halide of a compound of the general formula [21].

  In the method using an alkylating agent, the solvent used is not particularly limited as long as it does not adversely influence the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl Ethers such as ether; ketones such as acetone and 2-butanone; nitriles such as acetonitrile; esters such as ethyl acetate and butyl acetate; Rusuruhokishido is like sulfoxides such as may be used in these mixed.

  Examples of the phase transfer catalyst optionally used in this reaction include quaternary ammonium salts such as tetramethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride and tetrabutylammonium bromide. The amount of the phase transfer catalyst used is 0.01 mol or more, preferably 0.1 to 5 times the mol of the compound of the general formula [21].

Examples of the base used in this reaction include inorganic bases such as sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine, pyridine, dimethylaminopyridine and N-methylmorpholine. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [21].
Examples of the alkylating agent used in this reaction include methyl iodide, ethyl iodide, dimethyl sulfate, 2-bromo-2-methylpropane, benzyl chloride, and benzyl bromide. The amount of the alkylating agent used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [21].
This reaction may be usually carried out at 0 to 170 ° C. for 1 minute to 24 hours.

In the method via an acid halide, the compound of the general formula [21] is reacted with, for example, thionyl chloride or oxalyl chloride to form an acid halide, and then in the presence or absence of a base, methanol, ethanol and What is necessary is just to make it react with alcohols, such as benzyl alcohol.
In this reaction, the solvent used is not particularly limited as long as it does not adversely influence the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as methylene chloride, chloroform and dichloroethane. Hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; nitriles such as acetonitrile; esters such as ethyl acetate and butyl acetate And sulfoxides such as dimethyl sulfoxide, etc., and these may be used as a mixture.

Examples of the base used as desired in this reaction include inorganic bases such as sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine, pyridine, dimethylaminopyridine and N-methylmorpholine. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [21].
This reaction may be usually carried out at 0 to 170 ° C. for 1 minute to 24 hours.

  As a compound of general formula [23], for example, methyl = 2-amino-4-iodobenzoate is known.

(A-2)
The compound of general formula [23] can be produced by reducing the compound of general formula [22]. This reaction was performed by Richard C. • Richard C. Larock et al., Comprehensive Organic Transformations, 2nd edition, pp. 823-827, 1999, John Wiley & Sons (John Wiley & Sons, INC.) Or a method analogous thereto. Specific examples include a reduction reaction using a metal such as iron or zinc.

  In this reaction, the solvent used is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; Halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; Aromatic carbonization such as benzene, toluene and xylene Hydrogen; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; nitriles such as acetonitrile; acetone and 2 Ketones such as butanone; and esters such as ethyl acetate and butyl acetate and the like, may be used which are mixed.

Examples of the metal used in this reaction include iron, zinc, tin, and tin (II) chloride. The amount of the metal used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [22].
Examples of the acid that is optionally used in this reaction include hydrogen chloride, hydrogen bromide, and acetic acid. The amount of the acid used may be 0.001 to 100 times (W / V), preferably 0.01 to 20 times (W / V) of the compound of the general formula [22].
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.

(A-3)
The compound of the general formula [23] can be produced by reducing the compound of the general formula [22] according to the production method (2-2).

(A-4)
The compound of the general formula [2] can be produced by reacting the compound of the general formula [23] with the compound of the general formula [13] according to the production method (8-1) or (8-2). it can.

(A-5)
As the compound of the general formula [24a], for example, 4- (methanesulfonamido) phenylboronic acid, benzofuran-2-boronic acid, 3-methoxyphenylboronic acid and the like are known. As the compound of the general formula [24b], for example, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinoline and the like are known. In addition, the compounds of the general formulas [24a] and [24b] can be produced from the corresponding halogeno isomers according to, for example, the method described in JP-A-2003-206290.

The compound of the general formula [2] can be produced, for example, by the method described in Organic Letters, Vol. 3, pages 2077-2079, 2001. Specifically, in the presence or absence of a base, in the presence or absence of myristic acid, in the presence of a metal catalyst, the compound of general formula [23] is converted to the compound of general formula [24a] or [24b]. It can be produced by reacting.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, water; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; benzene , Aromatic hydrocarbons such as toluene and xylene; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane Ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; acetonitrile What nitriles, esters such as ethyl acetate and butyl acetate; and the like sulfoxides such as dimethyl sulfoxide and the like, may be used which are mixed.

Bases optionally used in this reaction include, for example, inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; and organic bases such as triethylamine, diisopropylethylamine, tributylamine and 2,6-lutidine. It is done. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [23].
Examples of the metal catalyst used in this reaction include copper (II) acetate and mercury (II) acetate. The usage-amount of a metal catalyst is 0.00001-1 times mole with respect to the compound of General formula [23], Preferably, what is necessary is just 0.001-1 times mole.
The amount of myristic acid used as desired in this reaction may be 0.001 to 50 times mol, preferably 0.1 to 2 times mol, of the compound of general formula [23].
The amount of the compound of the general formulas [24a] and [24b] used may be 1 to 50 times mol, preferably 1 to 2 times mol for the compound of the general formula [23].
This reaction is preferably carried out at 10 to 170 ° C. for 1 minute to 96 hours in an inert gas (eg, nitrogen, argon) atmosphere.

「式中、Ｒ^１ａ、Ｒ^３、Ｒ^５、Ｘ^１、Ｘ^４ｃ、Ｘ^５およびＬ^１は、前記と同様の意味を示す。」[Production method B]

“Wherein R ^1a , R ³ , R ⁵ , X ¹ , X ^4c , X ⁵ and L ¹ have the same meaning as described above.

  The compound of the general formula [7] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [25a] or the general formula [25b] according to the production method 1.

「式中、Ｒ^１ａ、Ｒ^３、Ｘ^１およびＬ^３は、前記と同様の意味を示す。」[Production Method C]

“Wherein R ^1a , R ³ , X ¹ and L ³ have the same meaning as described above.”

  As a compound of general formula [26], for example, 2-chloro-4-nitrobenzoic acid is known.

(C-1)
The compound of the general formula [27] can be produced by reacting the compound of the general formula [26] with the compound of the general formula [16] according to the production method (8-1) or (8-2). it can.

(C-2)
The compound of the general formula [28] can be produced by esterifying the compound of the general formula [27] according to the production method (A-1).

(C-3)
The compound of the general formula [9] can be produced by reducing the compound of the general formula [28] according to the production method (2-2) or (A-2).

「式中、Ｒ^６は、フェノール性ヒロドキシル保護基またはチオール保護基を；Ｘ^３ｅは、酸素原子または硫黄原子を；Ｒ^１ａ、Ｒ^３、Ｘ^１およびＬ^３は、前記と同様の意味を示す。」[Production Method D]

“Wherein R ⁶ represents a phenolic hydroxyl protecting group or a thiol protecting group; X ^3e represents an oxygen atom or a sulfur atom; R ^1a , R ³ , X ¹ and L ³ represent the same meaning as described above. . "

  As a compound of the general formula [29], for example, methyl = 2-iodo-4-methoxybenzoate is known.

(D-1)
The compound of the general formula [30] can be produced by reacting the compound of the general formula [29] with the compound of the general formula [16] according to the production method (8-1) or (8-2). it can.

(D-2)
The compound of the general formula [10a] can be produced by deprotecting the compound of the general formula [30].
When R ⁶ is a phenolic hydroxyl protecting group, compounds of general formula [10a] W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 249-287, 1999, John Wiley & Sons (John Wiley & Sons, INC.).
When R ⁶ is a thiol protecting group, the compound of the general formula [10a] is, for example, W.I. W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 454-493, 1999, John Wiley & Sons (John Wiley & Sons, INC.).

「式中、Ｒ^１ａ、Ｒ^４、Ｒ^５、Ｘ^４、Ｘ^５およびＬ^１は、前記と同様の意味を示す。」[Production Method E]

“In the formula, R ^1a , R ⁴ , R ⁵ , X ⁴ , X ⁵ and L ¹ have the same meaning as described above.”

  The compound of the general formula [31a] can be produced by reacting the compound of the general formula [22] with the compound of the general formula [3a] or the general formula [3b] according to the production method 1.

「式中、Ｒ^１ａ、Ｒ^４ａおよびＬ^１は、前記と同様の意味を示す。」[Production Method F]

“Wherein R ^1a , R ^4a and L ¹ have the same meaning as described above.”

  The compound of general formula [31b] can be produced by reacting the compound of general formula [22] with the compound of general formula [4] according to the production method (2-1).

「式中、Ｒ^１ａ、Ｒ^４、Ｘ^３ｂ、Ｘ^４ｃおよびＬ^１は、前記と同様の意味を示す。」[Production method G]

“In the formula, R ^1a , R ⁴ , X ^3b , X ^4c and L ¹ have the same meaning as described above.”

  The compound of the general formula [31c] can be produced by reacting the compound of the general formula [22] with the compound of the general formula [5] according to the production method (2-1).

「式中、Ｒ^１ａ、Ｒ^４、Ｘ^２ａおよびＬ^１は、前記と同様の意味を示す。」[Production Method H]

“Wherein R ^1a , R ⁴ , X ^2a and L ¹ have the same meaning as described above.”

  The compound of the general formula [31d] can be produced by reacting the compound of the general formula [22] with the compound of the general formula [6] according to the production method (2-1) or (4-2). it can.

「式中、Ｒ^１ａ、Ｒ^４およびＸ^２は、前記と同様の意味を示す。」[Production Method I]

“Wherein R ^1a , R ⁴ and X ² have the same meaning as described above.”

  The compound of the general formula [12] can be produced by reducing the compound of the general formula [31] according to the production method (2-2) or (A-2).

「式中、Ｌ^４は、脱離基を；Ｒ^１ａ、Ｒ^４、Ｘ^３ｃおよびＸ^４ｄは、前記と同様の意味を示す。」[Production Method J]

“Wherein L ⁴ represents a leaving group; R ^1a , R ⁴ , X ^3c and X ^4d have the same meaning as described above.”

As a compound of the general formula [32], for example, methyl = 4- (bromomethyl) -2-nitrobenzoate is known. Further, methyl 4- (bromomethyl) -2-nitrobenzoate is described in Journal of Medicinal Chemistry, Vol. 29, pages 589-591, 1986. 4- It can be produced by esterifying (bromomethyl) -2-nitrobenzoic acid according to a conventional method.
As compounds of the general formula [33], for example, aniline, phenol, benzenethiol and the like are known.

(J-1)
The compound of general formula [34] can be produced by reacting the compound of general formula [32] with the compound of general formula [33] according to the production method (7-1).

(J-2)
The compound of the general formula [15a] can be produced by reducing the compound of the general formula [34] according to the production method (2-2) or (A-2).

「式中、Ｒ^２ａ、Ｒ^３ａ、Ｒ^４、Ｘ^２ｃおよびＬ^２は、前記と同様の意味を示す。」[Production method K]

“Wherein R ^2a , R ^3a , R ⁴ , X ^2c and L ² have the same meaning as described above.”

As a compound of general formula [35], for example, 1-methyl-2-nitro-4-phenoxybenzene and the like are known.
As a compound of the general formula [36], for example, 3-amino-4-methylbenzophenone is known.

(K-1)
The compound of the general formula [36] can be produced by reducing the compound of the general formula [35] according to the production method (A-2).

(K-2)
The compound of the general formula [37] can be produced by reacting the compound of the general formula [36] with the compound of the general formula [13] according to the production method (8-1) or (8-2). it can.

(K-3)
The compound of the general formula [17a] can be produced by protecting the amino group of the compound of the general formula [37]. This reaction is W. Greene et al., Protective Groups in Organic Synthesis, 3rd edition, pages 494-615, 1999, John Wiley & Sons (John Wiley & Sons, INC.) Or a method analogous thereto. For example, in the case of an amide type or urethane type protecting group, specific examples include a method using an acid halide or a method using an acid anhydride.

In the method using an acid halide, the desired acid halide and the compound of the general formula [37] may be reacted in the presence or absence of a base.
In this reaction, the solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as methylene chloride, chloroform and dichloroethane. Hydrocarbons; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether Ketones such as acetone and 2-butanone; nitriles such as acetonitrile; esters such as ethyl acetate and butyl acetate; and dimethyl sulfoxide What sulfoxides, and the like, may be used which are mixed.

Bases optionally used in this reaction include, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, and triethylamine, pyridine, dimethylaminopyridine and N-methylmorpholine. And organic bases. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [37].
Examples of the acid halide used in this reaction include acetyl chloride, benzoyl chloride, trimethylacetyl chloride, methoxymethyl chloride, benzyloxymethyl chloride, and benzyloxymethylcarbonyl chloride. The amount of the acid halide used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [37].
This reaction may be usually carried out at 0 to 170 ° C. for 1 minute to 24 hours.

In the method using an acid anhydride, the desired acid anhydride and the compound of the general formula [37] may be reacted in the presence or absence of a base.
In this reaction, the solvent used is not particularly limited as long as it does not adversely influence the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as methylene chloride, chloroform and dichloroethane. Hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and diethylene glycol diethyl ether; ketones such as acetone and 2-butanone; nitriles such as acetonitrile; esters such as ethyl acetate and butyl acetate And sulfoxides such as dimethyl sulfoxide, etc., and these may be used as a mixture.

Examples of the base used as desired in this reaction include inorganic bases such as sodium carbonate, potassium carbonate and cesium carbonate, and organic bases such as triethylamine, pyridine, dimethylaminopyridine and N-methylmorpholine. The amount of the base used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [37].
Examples of the acid anhydride used in this reaction include acetic anhydride, trichloroacetic anhydride, di-tert-butyl dicarbonate, and the like. The amount of the acid anhydride to be used may be 1 to 50 times mol, preferably 1 to 5 times mol, of the compound of the general formula [37].
This reaction may be usually carried out at 0 to 170 ° C. for 1 minute to 24 hours.

(K-4)
The compound of the general formula [38] can be produced by protecting the amino group of the compound of the general formula [36] according to the production method (K-3).

(K-5)
The compound of the general formula [18a] can be produced by oxidizing the compound of the general formula [38] according to the production method 11.

「式中、Ｌ^３ａは塩素原子、臭素原子またはヨウ素原子を；Ｒ^１ａ、Ｒ^２、Ｒ^４およびＸ^２は、前記と同様の意味を示す。」[Production Method L]

“Wherein L ^3a represents a chlorine atom, a bromine atom or an iodine atom; R ^1a , R ² , R ⁴ and X ² have the same meaning as described above.

(L-1)
The compound of the general formula [39] can be produced by deprotecting the compound of the general formula [12] according to the production method (14-1).

(L-2)
The compound of the general formula [39] can be produced by deprotecting the compound of the general formula [18] according to the production method (14-1) or (14-2).

(L-3)
The compound of the general formula [20a] can be produced by diazotizing the compound of the general formula [39] using nitrites and then reacting with a desired metal halide.

The diazonium salt of the compound of the general formula [39] can be produced by reacting the compound of the general formula [39] with nitrites in the presence of an acid.
In this reaction, the solvent used is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include water; ethers such as dioxane and tetrahydrofuran, organic acids such as acetic acid, and the like. You may mix and use.
Examples of the acid that is optionally used in this reaction include hydrochloric acid, sulfuric acid, nitric acid, and hydrobromic acid. The amount of the acid used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound of the general formula [39].
Examples of nitrites used in this reaction include sodium nitrite and potassium nitrite. The amount of nitrites used may be 1 to 2 times mol, preferably 1 to 1.5 times mol, of the compound of general formula [39].
This reaction may be usually carried out at −10 to 15 ° C. for 1 minute to 24 hours.

The compound of the general formula [20a] can be produced by reacting the diazonium salt of the compound of the general formula [39] with a metal halide.
In this reaction, the solvent used is not particularly limited as long as it does not adversely influence the reaction. Examples thereof include water; ethers such as dioxane and tetrahydrofuran, organic acids such as acetic acid, and the like. You may mix and use.
Examples of the metal halide used in this reaction include copper (I) chloride, copper (I) bromide, copper (I) iodide or potassium iodide. The amount of the metal halide used may be 1 to 10 times mol, preferably 1 to 3 times mol for the compound diazonium salt of the general formula [39].
This reaction may be usually carried out at −10 to 80 ° C. for 1 minute to 24 hours.

「式中、Ｒ^１ａ、Ｒ^４およびＸ^２は、前記と同様の意味を示す。」[Production method M]

“Wherein R ^1a , R ⁴ and X ² have the same meaning as described above.”

  The compound of the general formula [12] can be produced by esterifying the compound of the general formula [39] according to the production method (A-1).

「式中、Ｒ^１ａ、Ｒ^３、Ｘ^１、Ｘ^５およびＬ^１は、前記と同様の意味を示す。」[Production method N]

“Wherein R ^1a , R ³ , X ¹ , X ⁵ and L ¹ have the same meaning as described above.”

  As the compound of the general formula [43], for example, bis (pinacolato) diboron, bis (neopentylglylate) diboron and bis (hexyleneglycolate) diboron are known.

  The compound of the general formula [40] can be produced by reacting the compound of the general formula [2] with the compound of the general formula [43] according to the production method 1.

「式中、Ｒ^１ａ、Ｒ^４ｅおよびＬ^１は、前記と同様の意味を示す。」[Production method O]

“Wherein R ^1a , R ^4e and L ¹ have the same meaning as described above.”

  The compound of general formula [31e] can be produced by reacting the compound of general formula [22] with the compound of general formula [42] according to the production method (8-1).

  Among the compounds used in the above-described production method, a compound that can take the form of a salt can also be used as a salt. Examples of such salts include the same salts as the salts of the compound of the general formula [1].

  In the compound used in the above-described production method, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist, these isomers can also be used. Also, when solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used. In addition, in the compounds used in the above-described production method, a compound having a substituent that can be protected, for example, an amino group, a hydroxyl group, or a carboxyl group, is previously protected with a normal protecting group. In addition, after the reaction, these protecting groups can be removed by a method known per se.

  When the compound of the present invention is used as a pharmaceutical, formulation adjuvants such as excipients, carriers, and diluents that are usually used for formulation may be appropriately mixed. These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. Usually, for adults, oral administration or parenteral administration (for example, injection, infusion, administration to the rectal site, etc.), 0.01 to 1000 mg / kg is administered in 1 to several divided doses per day. Good.

  Next, the usefulness of the representative compounds of the present invention will be described in the following test examples.

Test Example 1 MMP-13 Production Inhibition Test 6.8 × 10 ³ human cartilage-derived cell lines SW1353 cells were suspended in 100 μL of Dulbecco's modified Eagle medium containing 10% fetal bovine serum, seeded in a 96-well plate, and cultured for 3 days. The medium was replaced with 0.2% lactalbumin hydrolyzate-containing Dulbecco's modified Eagle medium and cultured for 6 hours, and then the test compound was added, and 1 hour later, IL-1β was added to a final concentration of 10 ng / mL. The supernatant was collected 16 hours after stimulation, and the amount of MMP-13 produced in the culture supernatant was determined using an ELISA kit (Amersham). The inhibition rate was calculated from the production amount obtained in the presence of the test compound, with the production amount obtained in the absence of the test compound as 100%.
The results are shown in Table 6.

Test Example 2 Mouse type II collagen arthritis
Eight week old male DBA / 1J mice (Nippon Charles River) were used. Prepare an emulsion by adding an equal volume of 4 mg / mL bovine type II collagen (collagen technical workshop) dissolved in 0.01 mol / L acetic acid aqueous solution and Freund's complete adjuvant (chondrox) containing 1 mg / mL of tuberculosis-killed bacteria to make 0.1 mL Was injected intradermally into the ridge. The same treatment was performed 21 days later to induce arthritis. The test compound was suspended in an aqueous 0.5% methylcellulose solution, and 10 mg / kg was orally administered once a day from 21 days to 35 days later. The control group was similarly administered with a 0.5% methylcellulose aqueous solution. The strength of arthritis is 0 point for no change, 1 point for swelling of 1 or 2 finger joints or 1 point for light swelling of the carpal joint, only for the tarsal joint, apparent swelling of the carpal or carpal joint or 3 or more finger joints An arthritic score was scored with 2 points for swelling, 3 points for obvious swelling in the entire forelimb or hindlimb, and a total score of 12 for the total extremity. The degree of bone destruction was taken after 36 days with X-rays of the extremities, joints between the 2nd to 5th interphalangeal joints, 1st to 5th metacarpal and metatarsophalangeal joints, carpal, tarsal and ribs. And 0 or 0.5 depending on the presence or absence of osteoporosis in the vicinity of the joint, and the bone erosion image was evaluated as 0 for no change, 1 for partial bone destruction, and 2 for complete bone destruction. The maximum bone destruction score was 105 points. The suppression rate was calculated | required with the following formula | equation.
Inhibition rate (%) = 100− (score of test compound administration group / score of control group) × 100
The compound represented by Example 38 showed an arthritis and bone destruction inhibitory action.

Next, the present invention will be described with reference examples and examples, but the present invention is not limited to these examples.
The mixing ratio in the eluent is a volume ratio. Unless otherwise specified, the carrier in silica gel column chromatography is Fuji Silysia Chemical Ltd., B.I. W. Silica gel, BW-127ZH; The carrier in reverse phase silica gel column chromatography is YMC Co., Ltd., ODS-AM12S05-2520WT.
In each example, each abbreviation has the following meaning.
Ac: acetyl, Boc: ^{tert-butoxycarbonyl,} t Bu: tert-butyl, Bz: benzoyl, Et: ethyl, Me: methyl
DMSO-d ₆ : Heavy dimethyl sulfoxide

４−ブロモ−２−ニトロ安息香酸4.0gのアセトン40mL溶液に、室温で炭酸カリウム3.4gおよび硫酸ジメチル2.3mLを加え、50℃で1時間攪拌した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物に、水および酢酸エチルを加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、白色固体のメチル＝４−ブロモ−２−ニトロベンゾアート4.1gを得た。
¹H-NMR(CDCl₃)δ値：3.97(3H,s),7.85(1H,d,J=8.3Hz),8.07(1H,dd,J=8.3,2.0Hz),8.47(1H,d,J=2.0Hz).Reference example 1

To a 40 mL acetone solution of 4.0 g of 4-bromo-2-nitrobenzoic acid, 3.4 g of potassium carbonate and 2.3 mL of dimethyl sulfate were added at room temperature, and the mixture was stirred at 50 ° C. for 1 hour. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the resulting residue. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution, 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. -4.1 g of bromo-2-nitrobenzoate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.97 (3H, s), 7.85 (1H, d, J = 8.3 Hz), 8.07 (1H, dd, J = 8.3, 2.0 Hz), 8.47 (1H, d, J = 2.0Hz).

４−ブロモ−２−ニトロ安息香酸5.0gのＮ，Ｎ−ジメチルアセトアミド50mL溶液に、室温で炭酸カリウム41g、ベンジルトリエチルアンモニウムクロリド4.6gおよび２−ブロモ−２−メチルプロパン69mLを加え、55℃で10時間攪拌した。反応混合物を室温まで冷却した後、２−ブロモ−２−メチルプロパン12mLを加え、55℃で4時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、固形物をろ取し、白色固体のｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート3.0gを得た。
¹H-NMR(CDCl₃)δ値：1.55(9H,s),7.63(1H,d,J=8.3Hz),7.77(1H,dd,J=8.3,1.9Hz),7.95(1H,d,J=1.9Hz).Reference example 2

To a solution of 5.0 g of 4-bromo-2-nitrobenzoic acid in 50 mL of N, N-dimethylacetamide was added 41 g of potassium carbonate, 4.6 g of benzyltriethylammonium chloride and 69 mL of 2-bromo-2-methylpropane at room temperature. Stir for 10 hours. After the reaction mixture was cooled to room temperature, 12 mL of 2-bromo-2-methylpropane was added and stirred at 55 ° C. for 4 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solid was collected by filtration to obtain 3.0 g of white solid tert-butyl 4-bromo-2-nitrobenzoate.
¹ H-NMR (CDCl ₃ ) δ value: 1.55 (9H, s), 7.63 (1H, d, J = 8.3 Hz), 7.77 (1H, dd, J = 8.3, 1.9 Hz), 7.95 (1H, d, J = 1.9Hz).

メチル＝４−ブロモ−２−ニトロベンゾアート4.0gのメタノール20mLおよび酢酸20mL混液に、鉄粉2.6gを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、不溶物をろ去した。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、白色固体のメチル＝２−アミノ−４−ブロモベンゾアート2.0gを得た。
¹H-NMR(CDCl₃)δ値：3.89(3H,s),4.20(2H,s),7.26(1H,dd,J=8.3,2.1Hz),7.43(1H,d,J=2.1Hz),7.47(1H,d,J=8.3Hz).Reference example 3

To a mixed solution of methyl 4-bromo-2-nitrobenzoate (4.0 g) in methanol (20 mL) and acetic acid (20 mL), 2.6 g of iron powder was added, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and insoluble material was removed by filtration. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain 2.0 g of methyl 2-amino-4-bromobenzoate as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 3.89 (3H, s), 4.20 (2H, s), 7.26 (1H, dd, J = 8.3, 2.1 Hz), 7.43 (1H, d, J = 2.1 Hz) , 7.47 (1H, d, J = 8.3Hz).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート5.5gのメタノール28mLおよび酢酸28mL混液に、鉄粉3.0gを加え、1時間加熱還流した。反応混合物を室温まで冷却した後、飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、不溶物をろ去した。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色油状物のｔｅｒｔ−ブチル＝２−アミノ−４−ブロモベンゾアート4.3gを得た。
¹H-NMR(DMSO-d₆)δ値：1.52(9H,s),6.65(1H,dd,J=8.5,2.0Hz),6.78(2H,s),6.98(1H,d,J=2.0Hz),7.55(1H,d,J=8.5Hz).Reference example 4

To a mixed solution of tert-butyl 4-bromo-2-nitrobenzoate (5.5 g) in 28 mL of methanol and 28 mL of acetic acid, 3.0 g of iron powder was added and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and insoluble material was removed by filtration. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and tert-butyl = 2-amino was obtained as a pale yellow oil. 4.3 g of -4-bromobenzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52 (9H, s), 6.65 (1H, dd, J = 8.5, 2.0 Hz), 6.78 (2H, s), 6.98 (1H, d, J = 2.0) Hz), 7.55 (1H, d, J = 8.5Hz).

メチル＝２−アミノ−４−ブロモベンゾアート1.2gのトルエン12mL溶液に、室温で１−フルオロ−４−ヨードベンゼン1.5mL、炭酸セシウム3.4g、酢酸パラジウム12mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル32mgを加え、窒素雰囲気下、12時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム12mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル32mgを加え、窒素雰囲気下、12時間加熱還流した。反応混合物を室温まで冷却した後、水を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、淡黄色固体のメチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.20gを得た。
¹H-NMR(DMSO-d₆)δ値：3.86(3H,s),6.94(1H,dd,J=8.6,1.7Hz),7.04(1H,d,J=1.7Hz),7.24-7.35(4H,m),7.80(1H,d,J=8.6Hz),9.27(1H,s).Reference Example 5

To a 12 mL toluene solution of 1.2 g of methyl-2-amino-4-bromobenzoate, 1.5 mL of 1-fluoro-4-iodobenzene, 3.4 g of cesium carbonate, 12 mg of palladium acetate and rac-2,2′-bis ( Diphenylphosphino) -1,1′-binaphthyl (32 mg) was added, and the mixture was heated to reflux for 12 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 12 mg of palladium acetate and 32 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl were added, and the mixture was heated to reflux for 12 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Co., Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1] to obtain methyl 4-bromo-2- 0.20 g of (4-fluoroanilino) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.86 (3H, s), 6.94 (1H, dd, J = 8.6, 1.7 Hz), 7.04 (1H, d, J = 1.7 Hz), 7.24-7.35 ( 4H, m), 7.80 (1H, d, J = 8.6Hz), 9.27 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−ブロモベンゾアート1.0gのトルエン15mL溶液に、室温で１−フルオロ−４−ヨードベンゼン0.85mL、炭酸セシウム3.6g、酢酸パラジウム8mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル23mgを加え、窒素雰囲気下、6時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム8mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル23mgを加え、窒素雰囲気下、8時間加熱還流した。反応混合物を室温まで冷却した後、水を加え、不溶物をろ去した。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、淡黄色油状物のｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.55gを得た。
¹H-NMR(DMSO-d₆)δ値：1.56(9H,s),6.93(1H,dd,J=8.6,1.6Hz),7.04(1H,d,J=1.6Hz),7.23-7.35(4H,m),7.75(1H,d,J=8.6Hz),9.34(1H,s).Reference Example 6

To a solution of 1.0 g of tert-butyl-2-amino-4-bromobenzoate in 15 mL of toluene, 0.85 mL of 1-fluoro-4-iodobenzene, 3.6 g of cesium carbonate, 8 mg of palladium acetate and rac-2,2′- Bis (diphenylphosphino) -1,1′-binaphthyl (23 mg) was added, and the mixture was heated to reflux for 6 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 8 mg of palladium acetate and 23 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl were added, and the mixture was heated to reflux for 8 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 20: 1] to give tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate as a pale yellow oil. Obtained 0.55 g of art.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.56 (9H, s), 6.93 (1H, dd, J = 8.6, 1.6 Hz), 7.04 (1H, d, J = 1.6 Hz), 7.23-7.35 ( 4H, m), 7.75 (1H, d, J = 8.6Hz), 9.34 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート5.0gのエチレングリコールジメチルエーテル50mLおよび水15mL混液に、室温でビニルボロン酸ピナコールエステル2.7mL、炭酸カリウム2.3gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.80gを順次加え、窒素雰囲気下、4時間加熱還流した。反応混合物を室温まで冷却した後、トルエンおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート3.4gを得た。
¹H-NMR(DMSO-d₆)δ値：1.56(9H,s),5.34(1H,d,J=11.0Hz),5.81(1H,d,J=17.7Hz),6.65(1H,dd,J=17.7,11.0,Hz),6.94-6.96(1H,m),7.06-7.07(1H,m),7.18-7.23(2H,m),7.27-7.32(2H,m),7.82(1H,d,J=8.3Hz),9.31(1H,s).Reference Example 7

A mixture of 5.0 g of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate with 50 mL of ethylene glycol dimethyl ether and 15 mL of water was mixed with 2.7 mL of vinylboronic acid pinacol ester, 2.3 g of potassium carbonate and tetrakis (triphenyl) at room temperature. Phosphine) palladium (0) 0.80 g was sequentially added, and the mixture was heated to reflux for 4 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, toluene and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 20: 1], and tert-butyl = 2- (4 -Fluoroanilino) -4-vinylbenzoate 3.4g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.56 (9H, s), 5.34 (1H, d, J = 11.0 Hz), 5.81 (1H, d, J = 17.7 Hz), 6.65 (1H, dd, J = 17.7,11.0, Hz), 6.94-6.96 (1H, m), 7.06-7.07 (1H, m), 7.18-7.23 (2H, m), 7.27-7.32 (2H, m), 7.82 (1H, d , J = 8.3Hz), 9.31 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート8.8gのトルエン70mL溶液に、室温でフェニルボロン酸4.3g、炭酸水素ナトリウム6.1g、エタノール26mL、水13mLおよびテトラキス（トリフェニルホスフィン）パラジウム（０）1.7gを順次加え、3時間加熱還流した。反応混合物を室温まで冷却した後、水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、白色固体のｔｅｒｔ−ブチル＝２−ニトロ−４−フェニルベンゾアート7.8gを得た。
¹H-NMR(DMSO-d₆)δ値：1.52(9H,s),7.47-7.56(3H,m),7.81-7.83(2H,m),7.91(1H,d,J=8.1Hz),8.11(1H,dd,J=8.1,2.0Hz),8.27(1H,d,J=2.0Hz).Reference Example 8

To a 70 mL toluene solution of 8.8 g tert-butyl 4-bromo-2-nitrobenzoate at room temperature, 4.3 g phenylboronic acid, 6.1 g sodium bicarbonate, 26 mL ethanol, 13 mL water and tetrakis (triphenylphosphine) palladium (0 ) 1.7 g was sequentially added, and the mixture was heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, water was added. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain 7.8 g of white solid tert-butyl-2-nitro-4-phenylbenzoate.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52 (9H, s), 7.47-7.56 (3H, m), 7.81-7.83 (2H, m), 7.91 (1H, d, J = 8.1 Hz), 8.11 (1H, dd, J = 8.1,2.0Hz), 8.27 (1H, d, J = 2.0Hz).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート6.0gのＮ，Ｎ−ジメチルアセトアミド48mL溶液に、スチレン2.7mL、酢酸ナトリウム2.5g、テトラブチルアンモニウムブロミド3.2gおよび酢酸パラジウム0.22gを順次加え、窒素雰囲気下、90℃で3時間加熱攪拌した。反応混合物を室温まで冷却した後、スチレン0.45mLおよび酢酸パラジウム0.22gを加え、110℃で3時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、白色固体のｔｅｒｔ−ブチル＝２−ニトロ−４−（（Ｅ）−２−フェニルビニル）ベンゾアート3.8gを得た。
¹H-NMR(DMSO-d₆)δ値：1.51(9H,s),7.33-7.45(4H,m),7.59(1H,d,J=16.6Hz),7.66(2H,d,J=7.4Hz),7.84(1H,d,J=8.1Hz),7.98(1H,dd,J=8.1,1.5Hz),8.23(1H,d,J=1.5Hz).Reference Example 9

To a solution of 6.0 g of tert-butyl 4-bromo-2-nitrobenzoate in 48 mL of N, N-dimethylacetamide, 2.7 mL of styrene, 2.5 g of sodium acetate, 3.2 g of tetrabutylammonium bromide and 0.22 g of palladium acetate were sequentially added. The mixture was heated and stirred at 90 ° C. for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 0.45 mL of styrene and 0.22 g of palladium acetate were added, and the mixture was stirred at 110 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 20: 1] and tert-butyl-2-nitro-4-((E) -2-phenylvinyl) as a white solid. 3.8 g of benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.51 (9H, s), 7.33-7.45 (4H, m), 7.59 (1H, d, J = 16.6 Hz), 7.66 (2H, d, J = 7.4 Hz), 7.84 (1H, d, J = 8.1Hz), 7.98 (1H, dd, J = 8.1,1.5Hz), 8.23 (1H, d, J = 1.5Hz).

ｔｅｒｔ−ブチル＝２−ニトロ−４−フェニルベンゾアート7.5gのメタノール38mLおよび酢酸38mL懸濁液に、室温で鉄粉4.2gを加え、１時間加熱還流した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去した。得られた残留物に、飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、不溶物をろ去した。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、白色固体のｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート3.3gを得た。
¹H-NMR(DMSO-d₆)δ値：1.55(9H,s),6.64-6.68(2H,broad),6.81(1H,dd,J=8.4,1.7Hz),7.03(1H,d,J=1.7Hz),7.39-7.49(3H,m),7.60(2H,d,J=7.6Hz),7.72(1H,d,J=8.4Hz).Reference Example 10

To a suspension of 7.5 g of tert-butyl = 2-nitro-4-phenylbenzoate in 38 mL of methanol and 38 mL of acetic acid, 4.2 g of iron powder was added at room temperature, and the mixture was heated to reflux for 1 hour. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. To the obtained residue, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid substance was collected by filtration to obtain 3.3 g of white solid tert-butyl-2-amino-4-phenylbenzoate.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.55 (9H, s), 6.64-6.68 (2H, broad), 6.81 (1H, dd, J = 8.4, 1.7 Hz), 7.03 (1H, d, J = 1.7Hz), 7.39-7.49 (3H, m), 7.60 (2H, d, J = 7.6Hz), 7.72 (1H, d, J = 8.4Hz).

ｔｅｒｔ−ブチル＝２−ニトロ−４−（（Ｅ）−２−フェニルビニル）ベンゾアート3.7gのメタノール56mLおよび酢酸エチル56mL混液に、5％パラジウム−炭素0.74gを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去し、白色固体のｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート3.4gを得た。
¹H-NMR(CDCl₃)δ値：1.58(9H,s),2.79-2.91(4H,m),5.63(2H,s),6.44(1H,s),6.47(1H,dd,J=8.3,1.5Hz),7.17-7.21(3H,m),7.26-7.30(2H,m),7.72(1H,d,J=8.3Hz).Reference Example 11

To a mixture of tert-butyl 2-nitro-4-((E) -2-phenylvinyl) benzoate 3.7 g of methanol 56 mL and ethyl acetate 56 mL was added 5% palladium-carbon 0.74 g, and at room temperature under a hydrogen atmosphere. Stir for 2 hours. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 3.4 g of white solid tert-butyl-2-amino-4-phenethylbenzoate.
¹ H-NMR (CDCl ₃ ) δ value: 1.58 (9H, s), 2.79-2.91 (4H, m), 5.63 (2H, s), 6.44 (1H, s), 6.47 (1H, dd, J = 8.3 1.5Hz), 7.17-7.21 (3H, m), 7.26-7.30 (2H, m), 7.72 (1H, d, J = 8.3Hz).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート50mgのトリフルオロ酢酸1.0mL溶液を室温で16時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.4に調整した。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、白色固体の２−アミノ−４−フェネチル安息香酸30mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.73-2.86(4H,m),6.41(1H,d,J=8.2Hz),6.58(1H,s),7.15-7.29(5H,m),7.59(1H,d,J=8.2Hz).Reference Example 12

A solution of tert-butyl 2-amino-4-phenethylbenzoate (50 mg) in trifluoroacetic acid (1.0 mL) was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the obtained residue, and the pH was adjusted to 6.4 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 30 mg of 2-amino-4-phenethylbenzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.73-2.86 (4H, m), 6.41 (1H, d, J = 8.2 Hz), 6.58 (1H, s), 7.15-7.29 (5H, m), 7.59 (1H, d, J = 8.2Hz).

２−アミノ−４−フェネチル安息香酸1.7gの酢酸17mL、水17mLおよび塩酸2.1mL懸濁液に、4℃で亜硝酸ナトリウム0.58gの水3.0mL溶液を加え、同温度で15分間攪拌した。反応混合物を4℃でヨウ化カリウム2.3gの水20mL溶液に加え、室温で30分間攪拌した。減圧下で溶媒を留去し、酢酸エチルを加えた。有機層を分取し、5%チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル：酢酸＝６６：３３：１］で精製し、黄色固体の２−ヨード−４−フェネチル安息香酸1.5gを得た。
¹H-NMR(DMSO-d₆)δ値：2.88(4H,s),7.16-7.30(5H,s),7.33(1H,dd,J=8.0,1.3Hz),7.66(1H,d,J=8.0Hz),7.86(1H,d,J=1.3Hz),13.01-13.29(1H,broad).Reference Example 13

To a suspension of 1.7 g of 2-amino-4-phenethylbenzoic acid in 17 mL of acetic acid, 17 mL of water and 2.1 mL of hydrochloric acid, a solution of sodium nitrite 0.58 g in 3.0 mL of water was added at 4 ° C. and stirred at the same temperature for 15 minutes. The reaction mixture was added at 4 ° C. to a solution of 2.3 g of potassium iodide in 20 mL of water and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate was added. The organic layer was separated, washed successively with 5% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate: acetic acid = 66: 33: 1] to give 2-iodo-4 as a yellow solid. -1.5 g of phenethylbenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.88 (4H, s), 7.16-7.30 (5H, s), 7.33 (1H, dd, J = 8.0, 1.3 Hz), 7.66 (1H, d, J = 8.0Hz), 7.86 (1H, d, J = 1.3Hz), 13.01-13.29 (1H, broad).

２−クロロ−４−ニトロ安息香酸30gのＮ，Ｎ−ジメチルアセトアミド150mL溶液に、室温で４−フルオロアニリン29mL、銅粉2.8g、塩化銅（I）5.3gおよびＮ−メチルモルホリン33mLを加え、110〜120℃で10時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、1.0mol/L塩酸700mLおよび酢酸エチル700mLを加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、赤色固体の２−（４−フルオロアニリノ）−４−ニトロ安息香酸9.7gを得た。
¹H-NMR(DMSO-d₆)δ値：7.26-7.33(2H,m),7.37-7.42(2H,m),7.50(1H,dd,J=8.6,2.3Hz),7.66(1H,d,J=2.3Hz),8.11(1H,d,J=8.6Hz),9.69(1H,s).Reference Example 14

To a solution of 30 g of 2-chloro-4-nitrobenzoic acid in 150 mL of N, N-dimethylacetamide was added 29 mL of 4-fluoroaniline, 2.8 g of copper powder, 5.3 g of copper (I) chloride and 33 mL of N-methylmorpholine at room temperature. The mixture was stirred at 110 to 120 ° C. for 10 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and 700 mL of 1.0 mol / L hydrochloric acid and 700 mL of ethyl acetate were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 9.7 g of 2- (4-fluoroanilino) -4-nitrobenzoic acid as a red solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.26-7.33 (2H, m), 7.37-7.42 (2H, m), 7.50 (1H, dd, J = 8.6,2.3Hz), 7.66 (1H, d , J = 2.3Hz), 8.11 (1H, d, J = 8.6Hz), 9.69 (1H, s).

２−（４−フルオロアニリノ）−４−ニトロ安息香酸1.0gのＮ，Ｎ−ジメチルアセトアミド15mL溶液に、室温で炭酸カリウム9.9g、ベンジルトリエチルアンモニウムクロリド0.82gおよび２−ブロモ−２−メチルプロパン21mLを加え、55℃で4時間攪拌した。反応混合物を室温まで冷却した後、２−ブロモ−２−メチルプロパン21mLを加え、55℃で12時間攪拌した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、水および10％クエン酸水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝８：１］で精製し、赤色油状物のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ニトロベンゾアート1.1gを得た。
¹H-NMR(DMSO-d₆)δ値：1.59(9H,s),7.26-7.31(2H,m),7.38-7.41(2H,m),7.51(1H,dd,J=8.8,2.3Hz),7.66(1H,d,J=2.3Hz),8.06(1H,d,J=8.8Hz),9.44(1H,s).Reference Example 15

To a solution of 1.0 g of 2- (4-fluoroanilino) -4-nitrobenzoic acid in 15 mL of N, N-dimethylacetamide, 9.9 g of potassium carbonate, 0.82 g of benzyltriethylammonium chloride and 2-bromo-2-methylpropane at room temperature 21 mL was added and stirred at 55 ° C. for 4 hours. After the reaction mixture was cooled to room temperature, 21 mL of 2-bromo-2-methylpropane was added and stirred at 55 ° C. for 12 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with water and 10% aqueous citric acid solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 8: 1], and tert-butyl = 2- (4-fluoroanilino) -4-nitrobenzoate as a red oily substance. 1.1g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.59 (9H, s), 7.26-7.31 (2H, m), 7.38-7.41 (2H, m), 7.51 (1H, dd, J = 8.8, 2.3 Hz ), 7.66 (1H, d, J = 2.3Hz), 8.06 (1H, d, J = 8.8Hz), 9.44 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ニトロベンゾアート1.0gのメタノール5.0mLおよび酢酸エチル5.0mL混液に、5％パラジウム−炭素0.20gを加え、水素雰囲気下、室温で6時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去し、白色固体のｔｅｒｔ−ブチル＝４−アミノ−２−（４−フルオロアニリノ）ベンゾアート0.90gを得た。
¹H-NMR(DMSO-d₆)δ値：1.51(9H,s),5.78-5.82(2H,broad),5.97(1H,dd,J=8.8,2.1Hz),6.19(1H,d,J=2.1Hz),7.16-7.26(4H,m),7.54(1H,d,J=8.8Hz),9.43(1H,s).Reference Example 16

To a mixed solution of 1.0 g of tert-butyl = 2- (4-fluoroanilino) -4-nitrobenzoate with 5.0 mL of methanol and 5.0 mL of ethyl acetate was added 0.20 g of 5% palladium-carbon, and 6% at room temperature under a hydrogen atmosphere. Stir for hours. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.90 g of white solid tert-butyl 4-amino-2- (4-fluoroanilino) benzoate.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.51 (9H, s), 5.78-5.82 (2H, broad), 5.97 (1H, dd, J = 8.8, 2.1 Hz), 6.19 (1H, d, J = 2.1Hz), 7.16-7.26 (4H, m), 7.54 (1H, d, J = 8.8Hz), 9.43 (1H, s).

３−アミノ−４−メチルベンゾフェノン0.50g、１−フルオロ−４−ヨードベンゼン0.30mLおよび１，１’−ビス（ジフェニルホスフィノ）フェロセン0.16gのトルエン5mL溶液に、室温でナトリウム＝ｔｅｒｔ−ブトキシド0.25gおよび（１，１’−ビス（ジフェニルホスフィノ）フェロセン）パラジウム（II）ジクロリド＝塩化メチレンコンプレックス0.077gを加え、窒素雰囲気下、100℃で1時間攪拌した。反応混合物を室温まで冷却した後、シリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、茶褐色油状物の３−（４−フルオロアニリノ）−４−メチルベンゾフェノン0.59gを得た。
¹H-NMR(CDCl₃)δ値：2.33(3H,s),6.98-7.00(4H,m),7.25-7.30(2H,m),7.43-7.47(2H,m),7.53-7.56(2H,m),7.76-7.78(2H,m).Reference Example 17

To a solution of 3-amino-4-methylbenzophenone 0.50 g, 1-fluoro-4-iodobenzene 0.30 mL and 1,1′-bis (diphenylphosphino) ferrocene 0.16 g in toluene 5 mL at room temperature, sodium tert-butoxide 0.25 g and (1,1′-bis (diphenylphosphino) ferrocene) palladium (II) dichloride = methylene chloride complex 0.077 g were added, and the mixture was stirred at 100 ° C. for 1 hour in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to give 0.59 g of brown oily 3- (4-fluoroanilino) -4-methylbenzophenone. Got.
¹ H-NMR (CDCl ₃ ) δ value: 2.33 (3H, s), 6.98-7.00 (4H, m), 7.25-7.30 (2H, m), 7.43-7.47 (2H, m), 7.53-7.56 (2H , m), 7.76-7.78 (2H, m).

３−（４−フルオロアニリノ）−４−メチルベンゾフェノン0.50gのＮ，Ｎ−ジメチルホルムアミド5.0mL溶液に、氷冷下で60％水素化ナトリウム79mgおよびアセチルクロリド0.14mLを順次加え、室温で4時間攪拌した。反応混合物を氷冷下まで冷却した後、60％水素化ナトリウム79mgおよびアセチルクロリド0.14mLを順次加え、室温で5時間30分間攪拌した。反応混合物に酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、橙色油状のＮ−（５−ベンゾイル−２−メチルフェニル）−Ｎ−（４−フルオロフェニル）アセトアミド82mgを得た。
¹H-NMR(CDCl₃)δ値：2.01-2.14(3H,m),2.31-2.42(3H,m),7.00-7.10(2H,m),7.24-7.28(2H,m),7.44-7.80(8H,m).Reference Example 18

To a solution of 0.50 g of 3- (4-fluoroanilino) -4-methylbenzophenone in 5.0 mL of N, N-dimethylformamide, 79 mg of 60% sodium hydride and 0.14 mL of acetyl chloride were sequentially added under ice-cooling. Stir for hours. After the reaction mixture was cooled to ice cooling, 79% sodium hydride (79 mg) and acetyl chloride (0.14 mL) were sequentially added, and the mixture was stirred at room temperature for 5 hours and 30 minutes. Ethyl acetate and 1.0 mol / L hydrochloric acid were added to the reaction mixture. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Co., Ltd., PSQ100B (spherical), eluent: hexane: ethyl acetate = 2: 1] to give N- (5-benzoyl-2-yl ester) as an orange oil. 82 mg of methylphenyl) -N- (4-fluorophenyl) acetamide was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 2.01-2.14 (3H, m), 2.31-2.42 (3H, m), 7.00-7.10 (2H, m), 7.24-7.28 (2H, m), 7.44-7.80 (8H, m).

フェノール0.18gのＮ，Ｎ−ジメチルホルムアミド5.0mL溶液に、室温で炭酸カリウム0.50gおよびメチル＝４−（ブロモメチル）−２−ニトロベンゾアート0.50gを加え、同温度で10時間攪拌した。反応混合物に酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝６：１］で精製し、無色油状物のメチル＝２−ニトロ−４−（フェノキシメチル）ベンゾアート0.53gを得た。
¹H-NMR(CDCl₃)δ値：3.93(3H,s),5.17(2H,s),6.95-7.03(3H,m),7.30-7.34(2H,m),7.72-7.79(2H,m),7.99(1H,s).Reference Example 19

To a solution of 0.18 g of phenol in 5.0 mL of N, N-dimethylformamide was added 0.50 g of potassium carbonate and 0.50 g of methyl 4- (bromomethyl) -2-nitrobenzoate at room temperature, and the mixture was stirred at the same temperature for 10 hours. Ethyl acetate and 1.0 mol / L hydrochloric acid were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 6: 1] to obtain 0.53 g of colorless oily methyl = 2-nitro-4- (phenoxymethyl) benzoate. .
¹ H-NMR (CDCl ₃ ) δ value: 3.93 (3H, s), 5.17 (2H, s), 6.95-7.03 (3H, m), 7.30-7.34 (2H, m), 7.72-7.79 (2H, m ), 7.99 (1H, s).

メチル＝４−（ブロモメチル）−２−ニトロベンゾアート1.0gのＮ，Ｎ−ジメチルホルムアミド10mL溶液に、室温で炭酸カリウム1.0gおよびベンゼンチオール0.39mLを加え、同温度で7時間攪拌した。反応混合物に酢酸エチルを加え、不溶物をろ去し、水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、淡黄色油状物のメチル＝２−ニトロ−４−（（フェニルチオ）メチル）ベンゾアート0.70gを得た。
¹H-NMR(CDCl₃)δ値：3.86(3H,s),4.27(2H,s),6.60-6.74(5H,m),7.15-7.19(2H,m),7.82(1H,d,J=8.3Hz).Reference Example 20

To a solution of 1.0 g of methyl 4- (bromomethyl) -2-nitrobenzoate in 10 mL of N, N-dimethylformamide was added 1.0 g of potassium carbonate and 0.39 mL of benzenethiol at room temperature, and the mixture was stirred at the same temperature for 7 hours. Ethyl acetate was added to the reaction mixture, the insoluble material was removed by filtration, and water was added. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 4: 1], and 0.70 g of methyl 2-nitro-4-((phenylthio) methyl) benzoate as a pale yellow oily substance. Got.
¹ H-NMR (CDCl ₃ ) δ value: 3.86 (3H, s), 4.27 (2H, s), 6.60-6.74 (5H, m), 7.15-7.19 (2H, m), 7.82 (1H, d, J = 8.3Hz).

メチル＝２−ニトロ−４−（フェノキシメチル）ベンゾアート0.66gのメタノール6.6mLおよび酢酸2.0mL混液に、鉄粉0.38gを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をジエチルエーテル6.6mLに溶解し、氷冷下で塩酸0.2mLを加え、固形物をろ取し、白色固体のメチル＝２−アミノ−４−（フェノキシメチル）ベンゾアート塩酸塩0.58gを得た。
¹H-NMR(DMSO-d₆)δ値：3.78(3H,s),4.40-4.80(2H,broad),5.03(2H,s),6.61(1H,dd,J=8.3,1.7Hz),6.86(1H,s),6.92-7.00(3H,m),7.27-7.32(2H,m),7.71(1H,d,J=8.3Hz).Reference Example 21

To a mixture of 6.6 mL of methyl 2-nitro-4- (phenoxymethyl) benzoate 0.66 g of methanol and 2.0 mL of acetic acid, 0.38 g of iron powder was added and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 6.6 mL of diethyl ether, 0.2 mL of hydrochloric acid was added under ice-cooling, the solid was collected by filtration, and methyl 2-amino-4- (phenoxymethyl) benzoate hydrochloride as a white solid 0.58 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.78 (3H, s), 4.40-4.80 (2H, broad), 5.03 (2H, s), 6.61 (1H, dd, J = 8.3, 1.7 Hz), 6.86 (1H, s), 6.92-7.00 (3H, m), 7.27-7.32 (2H, m), 7.71 (1H, d, J = 8.3Hz).

メチル＝２−ニトロ−４−（（フェニルチオ）メチル）ベンゾアート0.70gのメタノール7.0mLおよび酢酸2.1mL混液に、鉄粉0.39gを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加え、不溶物をろ去した。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をジエチルエーテル10mLに溶解し、氷冷下で、1.9mol/L塩化水素/酢酸エチル1.2mLを加え、固形物をろ取し、白色固体のメチル＝２−アミノ−４−（（フェニルチオ）メチル）ベンゾアート塩酸塩0.39gを得た。
¹H-NMR(DMSO-d₆)δ値：3.76(3H,s),4.13(2H,s),4.30-4.70(2H,broad),6.55(1H,dd,J=8.2,1.7Hz),6.79(1H,d,1.7Hz),7.15-7.19(1H,m),7.26-7.33(4H,m),7.62(1H,d,J=8.2Hz).Reference Example 22

To a mixed solution of methyl 2-nitro-4-((phenylthio) methyl) benzoate 0.70 g in methanol 7.0 mL and acetic acid 2.1 mL was added 0.39 g of iron powder, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 10 mL of diethyl ether, and 1.9 mol / L hydrogen chloride / ethyl acetate (1.2 mL) was added under ice-cooling. The solid matter was collected by filtration, and white solid methyl = 2-amino-4- 0.39 g of ((phenylthio) methyl) benzoate hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.76 (3H, s), 4.13 (2H, s), 4.30-4.70 (2H, broad), 6.55 (1H, dd, J = 8.2, 1.7 Hz), 6.79 (1H, d, 1.7Hz), 7.15-7.19 (1H, m), 7.26-7.33 (4H, m), 7.62 (1H, d, J = 8.2Hz).

１−メチル−２−ニトロ−４−フェノキシベンゼン5.7gのメタノール57mLおよび酢酸17mL混液に、鉄粉4.2gを加え、5時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加え、不溶物をろ去した。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をジエチルエーテル60mLに溶解し、氷冷下で塩酸2.1mLを加えた。固形物をろ取し、白色固体の２−メチル−５−フェノキシアニリン塩酸塩4.7gを得た。
¹H-NMR(DMSO-d₆)δ値：2.27(3H,s),6.82(1H,dd,J=8.3,2.4Hz),6.96(1H,d,J=2.4Hz),7.03(2H,d,J=7.5Hz),7.17(1H,t,J=7.5Hz),7.26(1H,d,J=8.3Hz),7.39-7.43(2H,m).Reference Example 23

To a mixed liquid of 57 mL of methanol and 17 mL of acetic acid of 5.7 g of 1-methyl-2-nitro-4-phenoxybenzene, 4.2 g of iron powder was added and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 60 mL of diethyl ether, and 2.1 mL of hydrochloric acid was added under ice cooling. The solid was collected by filtration to obtain 4.7 g of 2-methyl-5-phenoxyaniline hydrochloride as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.27 (3H, s), 6.82 (1H, dd, J = 8.3, 2.4 Hz), 6.96 (1H, d, J = 2.4 Hz), 7.03 (2H, d, J = 7.5Hz), 7.17 (1H, t, J = 7.5Hz), 7.26 (1H, d, J = 8.3Hz), 7.39-7.43 (2H, m).

２−メチル−５−フェノキシアニリン塩酸塩0.50gの塩化メチレン5.0mL溶液に、氷冷下、ピリジン0.34mLおよび無水酢酸0.24mLを加え、室温で6時間30分間攪拌した。減圧下に溶媒を留去し、得られた残留物に、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、白色固体のＮ−（２−メチル−５−フェノキシフェニル）アセトアミド0.44gを得た。
¹H-NMR(DMSO-d₆)δ値：2.18(3H,s),2.23(3H,s),6.74(1H,d,J=7.6Hz),6.92-6.98(1H,broad),7.00(2H,d,J=7.8Hz),7.06-7.13(2H,m),7.32(2H,t,J=7.8Hz),7.60(1H,s).Reference Example 24

To a solution of 0.50 g of 2-methyl-5-phenoxyaniline hydrochloride in 5.0 mL of methylene chloride was added 0.34 mL of pyridine and 0.24 mL of acetic anhydride under ice cooling, and the mixture was stirred at room temperature for 6 hours and 30 minutes. The solvent was distilled off under reduced pressure, and 1.0 mol / L hydrochloric acid and ethyl acetate were added to the obtained residue. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 2: 1], and white solid N- (2-methyl-5- 5 0.44 g of phenoxyphenyl) acetamide was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.18 (3H, s), 2.23 (3H, s), 6.74 (1H, d, J = 7.6 Hz), 6.92-6.98 (1H, broad), 7.00 ( 2H, d, J = 7.8Hz), 7.06-7.13 (2H, m), 7.32 (2H, t, J = 7.8Hz), 7.60 (1H, s).

Ｎ−（２−メチル−５−フェノキシフェニル）アセトアミド1.1gの２−メチル−２−プロパノール10mLおよび水20mL懸濁液に、室温で過マンガン酸カリウム1.4gおよび無水硫酸マグネシウム2.7gを加え、1時間加熱還流した。反応混合物を室温まで冷却した後、過マンガン酸カリウム0.72gを加え、1時間加熱還流した。反応混合物を室温まで冷却した後、過マンガン酸カリウム0.72gを加え、1時間加熱還流した。反応混合物を室温まで冷却した後、過マンガン酸カリウム0.36gを加え、1時間加熱還流した。反応混合物を室温まで冷却した後、エタノール5mLを加え、不溶物をろ去し、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の２−（アセトアミド）−４−フェノキシ安息香酸0.88gを得た。
¹H-NMR(DMSO-d₆)δ値：2.11(3H,s),6.68(1H,dd,J=8.9,2.4Hz),7.11-7.14(2H,m),7.23-7.27(1H,m),7.43-7.49(2H,m),7.99(1H,d,J=8.9Hz),8.20(1H,d,J=2.4Hz),11.29(1H,s),13.40-13.58(1H,broad).Reference Example 25

To a suspension of 1.1 g of N- (2-methyl-5-phenoxyphenyl) acetamide in 10 mL of 2-methyl-2-propanol and 20 mL of water was added 1.4 g of potassium permanganate and 2.7 g of anhydrous magnesium sulfate at room temperature. Heated to reflux for hours. The reaction mixture was cooled to room temperature, 0.72 g of potassium permanganate was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, 0.72 g of potassium permanganate was added, and the mixture was heated to reflux for 1 hour. After cooling the reaction mixture to room temperature, 0.36 g of potassium permanganate was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, 5 mL of ethanol was added, insoluble materials were filtered off, and 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to obtain 0.88 g of 2- (acetamido) -4-phenoxybenzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.11 (3H, s), 6.68 (1H, dd, J = 8.9, 2.4 Hz), 7.11-7.14 (2H, m), 7.23-7.27 (1H, m ), 7.43-7.49 (2H, m), 7.99 (1H, d, J = 8.9Hz), 8.20 (1H, d, J = 2.4Hz), 11.29 (1H, s), 13.40-13.58 (1H, broad) .

２−（アセトアミド）−４−フェノキシ安息香酸1.5gのヒドラジン一水和物5.0mL懸濁液を4時間加熱還流した。反応混合物を室温まで冷却した後、酢酸10mL、酢酸エチルおよび飽和塩化ナトリウム水溶液を加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、ジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の２−アミノ−４−フェノキシ安息香酸1.2gを得た。
¹H-NMR(DMSO-d₆)δ値：6.11(1H,dd,J=8.8,2.5Hz),6.20(1H,d,J=2.5Hz),7.06-7.09(2H,m),7.17-7.22(1H,m),7.40-7.45(2H,m),7.70(1H,d,J=8.8Hz).Reference Example 26

A suspension of 1.5 g of 2- (acetamido) -4-phenoxybenzoic acid in hydrazine monohydrate (5.0 mL) was heated to reflux for 4 hours. After the reaction mixture was cooled to room temperature, 10 mL of acetic acid, ethyl acetate and saturated aqueous sodium chloride solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to obtain 1.2 g of white solid 2-amino-4-phenoxybenzoic acid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.11 (1H, dd, J = 8.8,2.5 Hz), 6.20 (1H, d, J = 2.5 Hz), 7.06-7.09 (2H, m), 7.17- 7.22 (1H, m), 7.40-7.45 (2H, m), 7.70 (1H, d, J = 8.8Hz).

２−アミノ−４−フェノキシ安息香酸0.40gのＮ，Ｎ−ジメチルホルムアミド5.0mL溶液に、炭酸カリウム0.29gおよび硫酸ジメチル0.20mLを加え、室温で2時間攪拌した。反応混合物に、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄した後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、無色油状物のメチル＝２−アミノ−４−フェノキシベンゾアート0.33gを得た。
¹H-NMR(DMSO-d₆)δ値：3.76(3H,s),6.16(1H,dd,J=8.9,2.4Hz),6.23(1H,d,J=2.4Hz),6.76(2H,s),7.08-7.12(2H,m),7.20-7.24(1H,m),7.42-7.47(2H,m),7.70(1H,d,J=8.9Hz).Reference Example 27

To a solution of 0.40 g of 2-amino-4-phenoxybenzoic acid in 5.0 mL of N, N-dimethylformamide was added 0.29 g of potassium carbonate and 0.20 mL of dimethyl sulfate, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, which was washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1] to obtain 0.33 g of methyl 2-amino-4-phenoxybenzoate as a colorless oil.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.76 (3H, s), 6.16 (1H, dd, J = 8.9, 2.4 Hz), 6.23 (1H, d, J = 2.4 Hz), 6.76 (2H, s), 7.08-7.12 (2H, m), 7.20-7.24 (1H, m), 7.42-7.47 (2H, m), 7.70 (1H, d, J = 8.9Hz).

２−アミノ−４−フェノキシ安息香酸2.0gの水6.0mL、酢酸10mLおよび濃硫酸0.95mL懸濁液に、4℃で亜硝酸ナトリウム0.66gの水2.0mL溶液を加え、同温度で30分間攪拌した。反応混合物を同温度でヨウ化カリウム3.2gの水30mL溶液に滴下し、室温で3時間攪拌した。反応混合物に酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル：酢酸＝８０：２０：１］で精製し、赤色固体の２−ヨード−４−フェノキシ安息香酸1.6gを得た。
¹H-NMR(CDCl₃)δ値：6.98(1H,dd,J=8.7,2.4Hz),7.07-7.09(2H,m),7.22-7.26(1H,m),7.40-7.45(2H,m),7.64(1H,d,J=2.4Hz),8.04(1H,d,J=8.7Hz).Reference Example 28

To a suspension of 2-amino-4-phenoxybenzoic acid (2.0 g) in water (6.0 mL), acetic acid (10 mL) and concentrated sulfuric acid (0.95 mL) was added sodium nitrite (0.66 g) in water (2.0 mL) at 4 ° C, and the mixture was stirred at the same temperature for 30 minutes. did. The reaction mixture was added dropwise to a solution of 3.2 g of potassium iodide in 30 mL of water at the same temperature and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate: acetic acid = 80: 20: 1] to obtain 1.6 g of red solid 2-iodo-4-phenoxybenzoic acid.
¹ H-NMR (CDCl ₃ ) δ value: 6.98 (1H, dd, J = 8.7, 2.4 Hz), 7.07-7.09 (2H, m), 7.22-7.26 (1H, m), 7.40-7.45 (2H, m ), 7.64 (1H, d, J = 2.4Hz), 8.04 (1H, d, J = 8.7Hz).

４−フルオロフェニルボロン酸1.4g、無水酢酸銅（II）0.35gおよびミリスチン酸0.89gのトルエン20mL懸濁液に、２，６−ルチジン0.76mLを加え、室温で5分間攪拌した。反応混合物に、メチル＝２−アミノ−４−ヨードベンゾアート1.8gを加え、室温で3時間攪拌した。反応混合物に、４−フルオロフェニルボロン酸0.45gおよび無水酢酸銅（II）0.35gを加え、室温で8時間攪拌した。反応混合物に酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、淡黄色固体のメチル＝２−（４−フルオロアニリノ）−４−ヨードベンゾアート0.63gを得た。
¹H-NMR(CDCl₃)δ値：3.89(3H,s),7.03-7.11(3H,m),7.17-7.20(2H,m),7.34(1H,d,J=1.7Hz),7.61(1H,d,J=8.5Hz)9.32(1H,s).Reference Example 29

To a 20 mL suspension of 4-fluorophenylboronic acid 1.4 g, anhydrous copper (II) acetate 0.35 g and myristic acid 0.89 g in toluene, 0.76 mL of 2,6-lutidine was added and stirred at room temperature for 5 minutes. To the reaction mixture, 1.8 g of methyl-2-amino-4-iodobenzoate was added and stirred at room temperature for 3 hours. To the reaction mixture, 0.45 g of 4-fluorophenylboronic acid and 0.35 g of anhydrous copper (II) acetate were added and stirred at room temperature for 8 hours. Ethyl acetate and 1.0 mol / L hydrochloric acid were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 10: 1], and 0.63 g of methyl 2- (4-fluoroanilino) -4-iodobenzoate as a pale yellow solid. Got.
¹ H-NMR (CDCl ₃ ) δ value: 3.89 (3H, s), 7.03-7.11 (3H, m), 7.17-7.20 (2H, m), 7.34 (1H, d, J = 1.7 Hz), 7.61 ( (1H, d, J = 8.5Hz) 9.32 (1H, s).

メチル＝２−ヨード−４−メトキシベンゾアート2.7g、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル58mg、酢酸パラジウム20mgおよび炭酸セシウム6.0gのトルエン30mL懸濁液に、４−フルオロアニリン1.3mLを加え、窒素雰囲気下で5時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、白色固体のメチル＝２−（４−フルオロアニリノ）−４−メトキシベンゾアート2.2gを得た。
¹H-NMR(CDCl₃)δ値：3.73(3H,s),3.87(3H,s),6.29(1H,dd,J=8.9,2.4Hz),6.48(1H,d,J=2.4Hz),7.02-7.08(2H,m),7.19-7.23(2H,m),7.90(1H,d,J=8.9Hz),9.47(1H,s).Reference Example 30

2.7 g of methyl-2-iodo-4-methoxybenzoate, 58 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 20 mg of palladium acetate and 6.0 g of cesium carbonate in 30 mL of toluene Was added with 1.3 mL of 4-fluoroaniline and heated to reflux for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1], and white solid methyl = 2- (4-fluoroanis Rino) -4-methoxybenzoate (2.2 g) was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.73 (3H, s), 3.87 (3H, s), 6.29 (1H, dd, J = 8.9, 2.4 Hz), 6.48 (1H, d, J = 2.4 Hz) , 7.02-7.08 (2H, m), 7.19-7.23 (2H, m), 7.90 (1H, d, J = 8.9Hz), 9.47 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−メトキシベンゾアート2.2gを1.0mol/L三臭化ホウ素/塩化メチレン24mLに加え、室温で5時間攪拌した。反応混合物に飽和塩化ナトリウム水溶液および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、紫色固体のメチル＝２−（４−フルオロアニリノ）−４−ヒドロキシベンゾアート0.60gを得た。
¹H-NMR(CDCl₃)δ値：3.87(3H,s),5.04-5.18(1H,broad),6.19(1H,dd,J=8.8,2.3Hz),6.40(1H,d,J=2.3Hz),7.02-7.08(2H,m),7.18-7.23(2H,m),7.87(1H,d,J=8.8Hz),9.46(1H,s).Reference Example 31

Methyl 2- (4-fluoroanilino) -4-methoxybenzoate (2.2 g) was added to 1.0 mol / L boron tribromide / methylene chloride (24 mL), and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 5: 1], and purple solid methyl = 2- (4-fluoroanis Reno) -4-hydroxybenzoate 0.60 g was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.87 (3H, s), 5.04-5.18 (1H, broad), 6.19 (1H, dd, J = 8.8, 2.3 Hz), 6.40 (1H, d, J = 2.3 Hz), 7.02-7.08 (2H, m), 7.18-7.23 (2H, m), 7.87 (1H, d, J = 8.8Hz), 9.46 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート2.0gのトルエン20mL溶液に、エタノール6.0mL、水3.0mL、３−クロロフェニルボロン酸1.2g、炭酸ナトリウム1.7gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.23gを順次加え、窒素雰囲気下、3時間加熱還流した。反応混合物を室温まで冷却した後、水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、白色固体のｔｅｒｔ−ブチル＝４−（３−クロロフェニル）−２−ニトロベンゾアート0.70gを得た。
¹H-NMR(DMSO-d₆)δ値：1.52(9H,s),7.53-7.59(2H,m),7.77-7.82(1H,m),7.89-7.95(2H,m),8.15(1H,dd,J=8.1,1.6Hz),8.34(1H,d,J=1.6Hz).Reference Example 32

To a 20 mL toluene solution of 2.0 g of tert-butyl 4-bromo-2-nitrobenzoate, ethanol 6.0 mL, water 3.0 mL, 3-chlorophenylboronic acid 1.2 g, sodium carbonate 1.7 g and tetrakis (triphenylphosphine) palladium ( 0) 0.23 g was sequentially added, and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1], and white solid tert-butyl = 4- (3- 0.70 g of chlorophenyl) -2-nitrobenzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52 (9H, s), 7.53-7.59 (2H, m), 7.77-7.82 (1H, m), 7.89-7.95 (2H, m), 8.15 (1H , dd, J = 8.1,1.6Hz), 8.34 (1H, d, J = 1.6Hz).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート3.0gのトルエン24mL溶液に、エタノール9.0mL、水4.5mL、４−Ｎ−（メタンスルホンアミド）フェニルボロン酸2.6g、炭酸水素ナトリウム2.1gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.57gを加え、窒素雰囲気下、4時間30分間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。不溶物をろ去後、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、ヘキサンおよびジイソプロピルエーテルを加え、固形物をろ取し、白色固体のｔｅｒｔ−ブチル＝４−（４−Ｎ−（メタンスルホンアミド）フェニル）−２−ニトロベンゾアート3.9gを得た。
¹H-NMR(DMSO-d₆)δ値：1.51(9H,s),3.06(3H,s),7.32-7.37(2H,m),7.79-7.84(2H,m),7.89(1H,d,J=8.2Hz),8.07(1H,dd,J=8.2,1.8Hz),8.23(1H,d,J=1.8Hz),10.02-10.08(1H,broad).Reference Example 33

To a 24 mL toluene solution of 3.0 g of tert-butyl 4-bromo-2-nitrobenzoate, 9.0 mL of ethanol, 4.5 mL of water, 2.6 g of 4-N- (methanesulfonamido) phenylboronic acid, 2.1 g of sodium bicarbonate and Tetrakis (triphenylphosphine) palladium (0) 0.57 g was added, and the mixture was heated to reflux for 4 hours 30 minutes under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The insoluble material was removed by filtration, the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, hexane and diisopropyl ether were added, the solid was collected by filtration, and 3.9 g of tert-butyl 4- (4-N- (methanesulfonamido) phenyl) -2-nitrobenzoate as a white solid. Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.51 (9H, s), 3.06 (3H, s), 7.32-7.37 (2H, m), 7.79-7.84 (2H, m), 7.89 (1H, d , J = 8.2Hz), 8.07 (1H, dd, J = 8.2,1.8Hz), 8.23 (1H, d, J = 1.8Hz), 10.02--10.08 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート3.0gのトルエン24mL溶液に、エタノール9.0mL、水4.5mL、ｔｅｒｔ−ブチル＝３−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）フェニルカルボナート3.8g、炭酸水素ナトリウム2.1gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）0.57gを順次加え、窒素雰囲気下、6時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。不溶物をろ去後、有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝３：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝４−（３−（ｔｅｒｔ−ブトキシカルボニル）オキシフェニル）−２−ニトロベンゾアート3.6gを得た。
¹H-NMR(DMSO-d₆)δ値：1.51(9H,s),1.52(9H,s),7.29-7.34(1H,m),7.55-7.60(1H,m),7.70-7.76(2H,m),7.91(1H,d,J=8.0Hz),8.14(1H,dd,J=8.0,1.7Hz),8.32(1H,d,J=1.7Hz).Reference Example 34

To a 24 mL toluene solution of 3.0 g of tert-butyl 4-bromo-2-nitrobenzoate, ethanol 9.0 mL, water 4.5 mL, tert-butyl = 3- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) phenyl carbonate, 2.1 g of sodium hydrogen carbonate and 0.57 g of tetrakis (triphenylphosphine) palladium (0) were sequentially added, and the mixture was heated to reflux for 6 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The insoluble material was removed by filtration, the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 3: 1], and tert-butyl = 4- (3 3.6 g of (tert-butoxycarbonyl) oxyphenyl) -2-nitrobenzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.51 (9H, s), 1.52 (9H, s), 7.29-7.34 (1H, m), 7.55-7.60 (1H, m), 7.70-7.76 (2H , m), 7.91 (1H, d, J = 8.0Hz), 8.14 (1H, dd, J = 8.0, 1.7Hz), 8.32 (1H, d, J = 1.7Hz).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート3.0gのトルエン30mL溶液に、室温で、インドリン2.1mL、炭酸セシウム8.0g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル0.29g、トリス（ジベンジリデンアセトン）ジパラジウム（０）0.11gおよび酢酸パラジウム55mgを加え、窒素雰囲気下、3時間30分間加熱還流した。反応混合物を室温まで冷却した後、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル0.29g、トリス（ジベンジリデンアセトン）ジパラジウム（０）0.11gおよび酢酸パラジウム55mgを加え、窒素雰囲気下、3時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にトルエンを加え、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、黄色固体のｔｅｒｔ−ブチル＝４−（インドリン−１−イル）−２−ニトロベンゾアート2.0gを得た。
¹H-NMR(DMSO-d₆)δ値：1.48(9H,s),3.15(2H,t,J=8.4Hz),4.04(2H,t,J=8.4Hz),6.91(1H,t,J=7.4Hz),7.17(1H,t,J=7.4Hz),7.25-7.30(1H,m),7.35(1H,d,J=8.0Hz),7.50-7.55(2H,m),7.81(1H,d,J=8.6Hz).Reference Example 35

tert-Butyl 4-bromo-2-nitrobenzoate 3.0 g in toluene 30 mL solution at room temperature 2.1 mL indoline, cesium carbonate 8.0 g, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl 0.29 g of biphenyl, 0.11 g of tris (dibenzylideneacetone) dipalladium (0) and 55 mg of palladium acetate were added, and the mixture was heated to reflux for 3 hours 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 0.29 g of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 0.11 g of tris (dibenzylideneacetone) dipalladium (0) and 55 mg of palladium acetate were added, The mixture was heated to reflux for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 4- (indoline- 2.0 g of 1-yl) -2-nitrobenzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.48 (9H, s), 3.15 (2H, t, J = 8.4 Hz), 4.04 (2H, t, J = 8.4 Hz), 6.91 (1H, t, J = 7.4Hz), 7.17 (1H, t, J = 7.4Hz), 7.25-7.30 (1H, m), 7.35 (1H, d, J = 8.0Hz), 7.50-7.55 (2H, m), 7.81 ( (1H, d, J = 8.6Hz).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート0.50gのＮ，Ｎ−ジメチルアセトアミド5mL溶液に、室温で、３−ビニルアニソール0.37mL、トリエチルアミン0.47mLおよび酢酸パラジウム0.11gを加え、窒素雰囲気下、110℃で4時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、淡黄色固体のｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（３−メトキシフェニル）ビニル）−２−ニトロベンゾアート0.20gを得た。
¹H-NMR(DMSO-d₆)δ値：1.51(9H,s),3.81(3H,s),6.90-6.94(1H,m),7.20-7.27(2H,m),7.34(1H,t,J=7.9Hz),7.43(1H,d,J=16.6Hz),7.55(1H,d,J=16.6Hz),7.84(1H,d,J=8.0Hz),7.97(1H,d,J=7.8Hz),8.21(1H,s).Reference Example 36

To a solution of 0.50 g of tert-butyl 4-bromo-2-nitrobenzoate in 5 mL of N, N-dimethylacetamide was added 0.37 mL of 3-vinylanisole, 0.47 mL of triethylamine and 0.11 g of palladium acetate at room temperature. , And stirred at 110 ° C. for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 4-(( E) -2- (3-Methoxyphenyl) vinyl) -2-nitrobenzoate 0.20 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.51 (9H, s), 3.81 (3H, s), 6.90-6.94 (1H, m), 7.20-7.27 (2H, m), 7.34 (1H, t , J = 7.9Hz), 7.43 (1H, d, J = 16.6Hz), 7.55 (1H, d, J = 16.6Hz), 7.84 (1H, d, J = 8.0Hz), 7.97 (1H, d, J = 7.8Hz), 8.21 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−ニトロベンゾアート3.0gのＮ，Ｎ−ジメチルアセトアミド24mL溶液に、室温で、２，３−ジヒドロ−６−ビニルベンゾ［１，４］ジオキシン2.4g、Ｎ，Ｎ−ジシクロヘキシルメチルアミン4.0mLおよび酢酸パラジウム0.11gを加え、窒素雰囲気下、120℃で3時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加え、不溶物をろ去した。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、黄色固体のｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）ビニル）−２−ニトロベンゾアート1.5gを得た。
¹H-NMR(DMSO-d₆)δ値：1.50(9H,s),4.27(4H,s),6.90(1H,d,J=8.3Hz),7.11-7.16(1H,m),7.17-7.20(1H,m),7.23(1H,d,J=16.5Hz),7.45(1H,d,J=16.5Hz),7.81(1H,d,J=8.0Hz),7.89-7.93(1H,m),8.14(1H,s).Reference Example 37

To a solution of 3.0 g of tert-butyl 4-bromo-2-nitrobenzoate in 24 mL of N, N-dimethylacetamide at room temperature, 2.4 g of 2,3-dihydro-6-vinylbenzo [1,4] dioxin, N, N -Dichloromethylamine 4.0mL and palladium acetate 0.11g were added, and it stirred at 120 degreeC under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 4-((E ) -2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) vinyl) -2-nitrobenzoate (1.5 g) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.50 (9H, s), 4.27 (4H, s), 6.90 (1H, d, J = 8.3 Hz), 7.11-7.16 (1H, m), 7.17- 7.20 (1H, m), 7.23 (1H, d, J = 16.5Hz), 7.45 (1H, d, J = 16.5Hz), 7.81 (1H, d, J = 8.0Hz), 7.89-7.93 (1H, m ), 8.14 (1H, s).

ｔｅｒｔ−ブチル＝４−（３−クロロフェニル）−２−ニトロベンゾアート1.1gのメタノール11mLおよび酢酸エチル11mL混液に、10％パラジウム−炭素0.33gを加え、水素雰囲気下、室温で3時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物に、酢酸11mL、メタノール11mLおよび10％パラジウム−炭素0.33gを順次加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、白色固体のｔｅｒｔ−ブチル＝２−アミノ−４−（３−クロロフェニル）ベンゾアート0.70gを得た。
¹H-NMR(DMSO-d₆)δ値：1.55(9H,s),6.63-6.69(2H,broad),6.83(1H,dd,J=8.5,1.9Hz),7.06(1H,d,J=1.9Hz),7.46(1H,dt,J=7.8,1.6Hz),7.50(1H,t,J=7.8Hz),7.57(1H,dt,J=7.8,1.6Hz),7.63(1H,t,J=1.6Hz),7.73(1H,d,J=8.5Hz).Reference Example 38

To a mixed solution of tert-butyl 4- (3-chlorophenyl) -2-nitrobenzoate (1.1 g) in methanol (11 mL) and ethyl acetate (11 mL) was added 10% palladium-carbon (0.33 g), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, acetic acid (11 mL), methanol (11 mL), and 10% palladium-carbon (0.33 g) were sequentially added, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 0.70 g of white solid tert-butyl = 2-amino-4- (3-chlorophenyl) benzoate.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.55 (9H, s), 6.63-6.69 (2H, broad), 6.83 (1H, dd, J = 8.5, 1.9 Hz), 7.06 (1H, d, J = 1.9Hz), 7.46 (1H, dt, J = 7.8,1.6Hz), 7.50 (1H, t, J = 7.8Hz), 7.57 (1H, dt, J = 7.8,1.6Hz), 7.63 (1H, t , J = 1.6Hz), 7.73 (1H, d, J = 8.5Hz).

ｔｅｒｔ−ブチル＝４−（４−Ｎ−（メタンスルホンアミド）フェニル）−２−ニトロベンゾアート3.8gのメタノール19mL懸濁液に、酢酸19mLおよび鉄粉1.6gを順次加え、1時間加熱還流した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去し、飽和炭酸水素ナトリウム水溶液および酢酸エチルを加え、不溶物をろ去した。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体のｔｅｒｔ−ブチル＝２−アミノ−４−（４−Ｎ−（メタンスルホンアミド）フェニル）ベンゾアート2.8gを得た。
¹H-NMR(DMSO-d₆)δ値：1.54(9H,s),3.03(3H,s),6.61-6.68(2H,broad),6.79(1H,dd,J=8.5,1.9Hz),6.99(1H,d,J=1.9Hz),7.27-7.32(2H,m),7.56-7.61(2H,m),7.70(1H,d,J=8.5Hz),9.86-9.94(1H,broad).Reference Example 39

To a suspension of tert-butyl 4- (4-N- (methanesulfonamido) phenyl) -2-nitrobenzoate (3.8 g) in methanol (19 mL) were sequentially added 19 mL of acetic acid and 1.6 g of iron powder, and the mixture was heated to reflux for 1 hour. . The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and insoluble material was filtered off. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 2.8 g of tert-butyl = 2-amino-4- (4-N- (methanesulfonamido) phenyl) benzoate as a yellow solid. .
¹ H-NMR (DMSO-d ₆ ) δ value: 1.54 (9H, s), 3.03 (3H, s), 6.61-6.68 (2H, broad), 6.79 (1H, dd, J = 8.5, 1.9 Hz), 6.99 (1H, d, J = 1.9Hz), 7.27-7.32 (2H, m), 7.56-7.61 (2H, m), 7.70 (1H, d, J = 8.5Hz), 9.86-9.94 (1H, broad) .

ｔｅｒｔ−ブチル＝４−（３−（ｔｅｒｔ−ブトキシカルボニル）オキシフェニル）−２−ニトロベンゾアート3.5gのメタノール18mLおよび酢酸エチル18mL混液に、5％パラジウム−炭素0.70gを加え、水素雰囲気下、室温で3時間30分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、黄色油状物のｔｅｒｔ−ブチル＝２−アミノ−４−（３−（ｔｅｒｔ−ブトキシカルボニル）オキシフェニル）ベンゾアート3.2gを得た。
¹H-NMR(DMSO-d₆)δ値：1.51(9H,s),1.55(9H,s),6.64-6.69(2H,broad),6.82(1H,dd,J=8.4,1.8Hz),7.05(1H,d,J=1.8Hz),7.20-7.24(1H,m),7.38-7.42(1H,m),7.49-7.53(2H,m),7.73(1H,d,J=8.4Hz).Reference Example 40

tert-Butyl 4- (3- (tert-butoxycarbonyl) oxyphenyl) -2-nitrobenzoate 3.5 g of methanol 18 mL and ethyl acetate 18 mL were mixed with 5% palladium-carbon 0.70 g, and under a hydrogen atmosphere, The mixture was stirred at room temperature for 3 hours and 30 minutes. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 3.2 g of tert-butyl = 2-amino-4- (3- (tert-butoxycarbonyl) oxyphenyl) benzoate as a yellow oil.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.51 (9H, s), 1.55 (9H, s), 6.64-6.69 (2H, broad), 6.82 (1H, dd, J = 8.4, 1.8 Hz), 7.05 (1H, d, J = 1.8Hz), 7.20-7.24 (1H, m), 7.38-7.42 (1H, m), 7.49-7.53 (2H, m), 7.73 (1H, d, J = 8.4Hz) .

ｔｅｒｔ−ブチル＝４−（インドリン−１−イル）−２−ニトロベンゾアート1.9gのメタノール29mLおよび酢酸エチル29mL混液に、5％パラジウム−炭素0.58gを加え、水素雰囲気下、室温で3時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝８：１］で精製し、淡黄色固体のｔｅｒｔ−ブチル＝２−アミノ−４−（インドリン−１−イル）ベンゾアート1.20gを得た。
¹H-NMR(DMSO-d₆)δ値：1.52(9H,s),3.08(2H,t,J=8.3Hz),3.91(2H,t,J=8.3Hz),6.45(1H,dd,J=8.9,2.3Hz),6.52(1H,d,J=2.3Hz),6.56-6.63(2H,broad),6.78(1H,t,J=7.6Hz),7.08(1H,t,J=7.6Hz),7.18-7.26(2H,m),7.61(1H,d,J=8.9Hz).Reference Example 41

Add 0.58 g of 5% palladium-carbon to a mixture of 29 mL of methanol and 29 mL of ethyl acetate in 1.9 g of tert-butyl 4- (indoline-1-yl) -2-nitrobenzoate and stir at room temperature for 3 hours in a hydrogen atmosphere. did. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 8: 1], and tert-butyl-2-amino- of light yellow solid was obtained. 1.20 g of 4- (indoline-1-yl) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52 (9H, s), 3.08 (2H, t, J = 8.3 Hz), 3.91 (2H, t, J = 8.3 Hz), 6.45 (1H, dd, J = 8.9, 2.3Hz), 6.52 (1H, d, J = 2.3Hz), 6.56-6.63 (2H, broad), 6.78 (1H, t, J = 7.6Hz), 7.08 (1H, t, J = 7.6 Hz), 7.18-7.26 (2H, m), 7.61 (1H, d, J = 8.9Hz).

ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（３−メトキシフェニル）ビニル）−２−ニトロベンゾアート2.2gのメタノール22mLおよび酢酸エチル22mL混液に、10％パラジウム−炭素0.66gを加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝８：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝２−アミノ−４−（２−（３−メトキシフェニル）エチル）ベンゾアート1.6gを得た。
¹H-NMR(DMSO-d₆)δ値：1.52(9H,s),2.72-2.84(4H,m),3.72(3H,s),6.41(1H,dd,J=8.2,1.5Hz),6.46-6.54(2H,broad),6.56-6.59(1H,m),6.72-6.80(3H,m),7.15-7.20(1H,m),7.55(1H,d,J=8.2Hz).Reference Example 42

tert-Butyl = 4-((E) -2- (3-methoxyphenyl) vinyl) -2-nitrobenzoate 2.2 g of methanol 22 mL and ethyl acetate 22 mL were mixed with 10% palladium-carbon 0.66 g, hydrogen Stir for 2 hours at room temperature under atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 8: 1], and tert-butyl = 2-amino- 1.6 g of 4- (2- (3-methoxyphenyl) ethyl) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52 (9H, s), 2.72-2.84 (4H, m), 3.72 (3H, s), 6.41 (1H, dd, J = 8.2, 1.5 Hz), 6.46-6.54 (2H, broad), 6.56-6.59 (1H, m), 6.72-6.80 (3H, m), 7.15-7.20 (1H, m), 7.55 (1H, d, J = 8.2Hz).

ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）ビニル）−２−ニトロベンゾアート1.5gのメタノール15mLおよび酢酸エチル15mL混液に、10％パラジウム−炭素0.44gを加え、水素雰囲気下、室温で2時間30分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝２−アミノ−４−（（Ｅ）−２−（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）エチル）ベンゾアート1.3gを得た。
¹H-NMR(DMSO-d₆)δ値：1.52(9H,s),2.68-2.72(4H,m),4.17-4.21(4H,m),6.39(1H,dd,J=8.2,1.6Hz),6.47-6.53(2H,broad),6.56(1H,d,J=1.2Hz),6.63-6.66(1H,m),6.69-6.74(2H,m),7.54(1H,d,J=8.3Hz).Reference Example 43

tert-butyl = 4-((E) -2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) vinyl) -2-nitrobenzoate 1.5 g in a mixture of 15 mL methanol and 15 mL ethyl acetate Then, 0.44 g of 10% palladium-carbon was added, and the mixture was stirred at room temperature for 2 hours and 30 minutes in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 2-amino- 1.3 g of 4-((E) -2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) ethyl) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52 (9H, s), 2.68-2.72 (4H, m), 4.17-4.21 (4H, m), 6.39 (1H, dd, J = 8.2, 1.6Hz ), 6.47-6.53 (2H, broad), 6.56 (1H, d, J = 1.2Hz), 6.63-6.66 (1H, m), 6.69-6.74 (2H, m), 7.54 (1H, d, J = 8.3) Hz).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート1.2gのジオキサン12mL溶液に、室温で、酢酸カリウム0.97g、ビス（ピナコラート）ジボロン1.8gおよび（１，１’−ビス（ジフェニルホスフィノ）フェロセン）パラジウム（II）ジクロリド塩化メチレンコンプレックス0.14gを順次加え、2時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルを加え、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、白色固体のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾアート0.86gを得た。
¹H-NMR(DMSO-d₆)δ値：1.25(12H,s),1.56(9H,s),7.04(1H,d,J=7.9Hz),7.19-7.30(4H,m),7.34(1H,s),7.82(1H,d,J=7.9Hz),9.18(1H,s).Reference Example 44

To a 12 mL dioxane solution of 1.2 g of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate at room temperature, 0.97 g of potassium acetate, 1.8 g of bis (pinacolato) diboron and (1,1′-bis (Diphenylphosphino) ferrocene) palladium (II) dichloride methylene chloride complex 0.14 g was sequentially added and heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, the insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 20: 1], and tert-butyl = 2- (4- 0.86 g of fluoroanilino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.25 (12H, s), 1.56 (9H, s), 7.04 (1H, d, J = 7.9 Hz), 7.19-7.30 (4H, m), 7.34 ( 1H, s), 7.82 (1H, d, J = 7.9Hz), 9.18 (1H, s).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、室温で３−メトキシフェニルボロン酸49mg、炭酸ナトリウム57mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）31mgを加え、90℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、2.0mol/L水酸化ナトリウム水溶液1.0mLおよびエタノール6.0mLを加え、室温で1時間攪拌した。反応混合物に0.5mol/L塩酸を加え、固形物をろ取し、淡黄色固体の２−（４−フルオロアニリノ）−４−（３−メトキシフェニル）安息香酸10mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.79(3H,s),6.96(1H,dd,J=8.1,2.4Hz),7.05(1H,dd,J=8.4,1.6Hz),7.08(1H,t,J=1.9Hz),7.12(1H,d,J=7.8Hz),7.20-7.25(3H,m),7.34-7.39(3H,m),7.97(1H,d,J=8.3Hz).Example 1

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in N, N-dimethylacetamide 2.5 mL solution at room temperature 49 mg 3-methoxyphenylboronic acid 57 mg sodium carbonate and polymer supported bis (acetate) 31 mg of triphenylphosphine palladium (II) was added and stirred at 90 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 2.0 mL / L aqueous sodium hydroxide solution (1.0 mL) and ethanol (6.0 mL) were added, and the mixture was stirred at room temperature for 1 hour. 0.5 mol / L hydrochloric acid was added to the reaction mixture, and the solid substance was collected by filtration to obtain 10 mg of 2- (4-fluoroanilino) -4- (3-methoxyphenyl) benzoic acid as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.79 (3H, s), 6.96 (1H, dd, J = 8.1, 2.4 Hz), 7.05 (1H, dd, J = 8.4, 1.6 Hz), 7.08 ( 1H, t, J = 1.9Hz), 7.12 (1H, d, J = 7.8Hz), 7.20-7.25 (3H, m), 7.34-7.39 (3H, m), 7.97 (1H, d, J = 8.3Hz ).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、室温で４−フルオロフェニルボロン酸45mg、炭酸ナトリウム57mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）31mgを加え、90℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、1.0mol/L水酸化ナトリウム水溶液1.0mLおよびエタノール3.0mLを加え、室温で1時間攪拌した。反応混合物に6.0mol/L塩酸を加え、固形物をろ取し、シリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル：酢酸＝２０：１０：１］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（４−フルオロフェニル）安息香酸7.8mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.03(1H,d,J=8.5Hz),7.20-7.32(5H,m),7.36-7.39(2H,m),7.60-7.64(2H,m),7.97(1H,d,J=8.5Hz),9.60-9.75(1H,broad),13.00-13.30(1H,broad).Example 2

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in N, N-dimethylacetamide 2.5 mL solution at room temperature 45 mg 4-fluorophenylboronic acid 57 mg sodium carbonate and polymer supported bis (acetate) 31 mg of triphenylphosphine palladium (II) was added and stirred at 90 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 1.0 mL of a 1.0 mol / L aqueous sodium hydroxide solution and 3.0 mL of ethanol were added, and the mixture was stirred at room temperature for 1 hour. 6.0 mol / L hydrochloric acid was added to the reaction mixture, and the solid matter was collected by filtration and purified by silica gel column chromatography [Triconex, Flash Tube 2008, eluent; hexane: ethyl acetate: acetic acid = 20: 10: 1]. As a result, 7.8 mg of 2- (4-fluoroanilino) -4- (4-fluorophenyl) benzoic acid was obtained as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.03 (1H, d, J = 8.5 Hz), 7.20-7.32 (5H, m), 7.36-7.39 (2H, m), 7.60-7.64 (2H, m ), 7.97 (1H, d, J = 8.5Hz), 9.60-9.75 (1H, broad), 13.00-13.30 (1H, broad).

実施例２と同様にして、以下の化合物を得た。
２−（４−フルオロアニリノ）−４−（２−メトキシフェニル）安息香酸
¹H-NMR(DMSO-d₆)δ値：3.78(3H,s),6.85-6.90(1H,m),7.01(1H,t,J=7.6Hz),7.10(1H,d,J=8.3Hz),7.19-7.37(7H,m),7.91(1H,d,J=8.3Hz),9.52-9.63(1H,broad),12.98-13.10(1H,broad).Example 3

In the same manner as in Example 2, the following compounds were obtained.
2- (4-Fluoroanilino) -4- (2-methoxyphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.78 (3H, s), 6.85-6.90 (1H, m), 7.01 (1H, t, J = 7.6 Hz), 7.10 (1H, d, J = 8.3 Hz), 7.19-7.37 (7H, m), 7.91 (1H, d, J = 8.3Hz), 9.52-9.63 (1H, broad), 12.98-13.10 (1H, broad).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、室温で４−（トリフルオロメチル）フェニルボロン酸62mg、炭酸ナトリウム57mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）31mgを加え、90℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、2.0mol/L水酸化ナトリウム水溶液1.0mLおよびエタノール6.0mLを加え、室温で1時間攪拌した。反応混合物に0.5mol/L塩酸を加えた。固形物をろ取し、逆相シリカゲルカラムクロマトグラフィー［溶離液；50-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（４−（トリフルオロメチル）フェニル）安息香酸18mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.10(1H,dd,J=8.3,1.8Hz),7.20-7.24(2H,m),7.29(1H,d,J=1.8Hz),7.37-7.40(2H,m),7.80(4H,s),8.02(1H,d,J=8.3Hz),9.64(1H,s).Example 4

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in N, N-dimethylacetamide 2.5 mL solution at room temperature with 62 mg 4- (trifluoromethyl) phenylboronic acid, 57 mg sodium carbonate and polymer support Bis (acetate) triphenylphosphine palladium (II) 31 mg was added, and the mixture was stirred at 90 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 2.0 mL / L aqueous sodium hydroxide solution (1.0 mL) and ethanol (6.0 mL) were added, and the mixture was stirred at room temperature for 1 hour. 0.5 mol / L hydrochloric acid was added to the reaction mixture. The solid was collected by filtration and purified by reverse-phase silica gel column chromatography [eluent: 50-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino) -4- 18 mg of (4- (trifluoromethyl) phenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.10 (1H, dd, J = 8.3,1.8 Hz), 7.20-7.24 (2H, m), 7.29 (1H, d, J = 1.8 Hz), 7.37- 7.40 (2H, m), 7.80 (4H, s), 8.02 (1H, d, J = 8.3Hz), 9.64 (1H, s).

Examples 5-8
In the same manner as in Example 4, the compounds shown in Table 7 were obtained.

4- (2,4-Difluorophenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.92 (1H, dt, J = 8.6,1.6 Hz), 7.16-7.23 (4H, m), 7.32-7.36 (3H, m), 7.56 (1H, td , J = 8.6, 6.7Hz), 7.98 (1H, d, J = 8.2Hz), 9.60 (1H, s), 13.06-13.29 (1H, broad).

2- (4-Fluoroanilino) -4- (3- (trifluoromethyl) phenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.12 (1H, dd, J = 8.2,1.8 Hz), 7.20-7.24 (2H, m), 7.30 (1H, d, J = 1.8 Hz), 7.37- 7.41 (2H, m), 7.69 (1H, t, J = 7.6Hz), 7.76 (1H, d, J = 7.7Hz), 7.87-7.88 (2H, m), 8.01 (1H, d, J = 8.2Hz ), 9.64 (1H, s).

4- (Benzo-1,3-dioxol-5-yl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.05 (2H, s), 6.97-7.00 (2H, m), 7.06 (1H, dd, J = 8.2, 1.9 Hz), 7.15 (1H, d, J = 1.8Hz), 7.19 (1H, d, J = 1.7Hz), 7.20-7.24 (2H, m), 7.34-7.38 (2H, m), 7.93 (1H, d, J = 8.2Hz), 9.60 (1H , s).

4- (Benzofuran-2-yl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.25-7.30 (3H, m), 7.32-7.35 (2H, m), 7.37-7.40 (2H, m), 7.48 (1H, d, J = 0.9Hz ), 7.53 (1H, d, J = 1.7Hz), 7.61 (1H, dd, J = 8.2,0.7Hz), 7.66-7.67 (1H, m), 8.00 (1H, d, J = 8.2Hz), 9.67 (1H, s).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で４−メトキシフェニルボロン酸66mg、炭酸ナトリウム69mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）31mgを加え、加圧下で160℃、5分間攪拌した。反応混合物を室温まで冷却した後、加圧下で180℃、5分間攪拌した。反応混合物を室温まで冷却した後、加圧下で200℃、5分間攪拌した。反応混合物を室温まで冷却した後、加圧下で220℃、5分間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび0.5mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、2.0mol/L水酸化ナトリウム水溶液1.0mLおよびエタノール4.0mLを加え、室温で1時間30分間攪拌した。反応混合物に0.7mol/L塩酸および酢酸エチルを加え、有機層を分取し、減圧下で溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（４−メトキシフェニル）安息香酸19mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.78(3H,s),6.98-7.03(3H,m),7.19-7.25(3H,m),7.34-7.38(2H,m),7.50-7.55(2H,m),7.94(1H,d,J=8.3Hz),9.62(1H,s),12.86-13.25(1H,broad).Example 9

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in N, N-dimethylacetamide 3.0 mL solution at room temperature 66 mg 4-methoxyphenylboronic acid, 69 mg sodium carbonate and polymer supported bis (acetate) 31 mg of triphenylphosphine palladium (II) was added, and the mixture was stirred at 160 ° C. for 5 minutes under pressure. The reaction mixture was cooled to room temperature and then stirred at 180 ° C. for 5 minutes under pressure. The reaction mixture was cooled to room temperature and stirred under pressure at 200 ° C. for 5 minutes. The reaction mixture was cooled to room temperature and stirred under pressure at 220 ° C. for 5 minutes. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 0.5 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 2.0 mL / L aqueous sodium hydroxide solution (1.0 mL) and ethanol (4.0 mL) were added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. 0.7 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 50-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino) -4- ( 19 mg of 4-methoxyphenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.78 (3H, s), 6.98-7.03 (3H, m), 7.19-7.25 (3H, m), 7.34-7.38 (2H, m), 7.50-7.55 (2H, m), 7.94 (1H, d, J = 8.3Hz), 9.62 (1H, s), 12.86-13.25 (1H, broad).

実施例９と同様にして、以下の化合物を得た。
４−（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）−２−（４−フルオロアニリノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：4.26(4H,s),6.92(1H,dd,J=7.3,1.5Hz),6.98(1H,dd,J=8.4,1.8Hz),7.03-7.05(2H,m),7.17(1H,d,J=1.8Hz),7.21-7.26(2H,m),7.33-7.38(2H,m),7.92(1H,d,J=8.4Hz),9.60(1H,s),12.93-13.18(1H,broad).Example 10

In the same manner as in Example 9, the following compounds were obtained.
4- (2,3-Dihydrobenzo [1,4] dioxin-6-yl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 4.26 (4H, s), 6.92 (1H, dd, J = 7.3, 1.5Hz), 6.98 (1H, dd, J = 8.4, 1.8Hz), 7.03- 7.05 (2H, m), 7.17 (1H, d, J = 1.8Hz), 7.21-7.26 (2H, m), 7.33-7.38 (2H, m), 7.92 (1H, d, J = 8.4Hz), 9.60 (1H, s), 12.93-13.18 (1H, broad).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、室温で４−（メタンスルホニル）フェニルボロン酸86mg、炭酸ナトリウム69mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）31mgを加え、90℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、2.0mol/L水酸化ナトリウム水溶液1.0mLおよびエタノール6.0mLを加え、室温で1時間攪拌した。反応混合物に0.5mol/L塩酸および酢酸エチルを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；40-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（４−（メタンスルホニル）フェニル）安息香酸28mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.24(3H,s),7.11(1H,d,J=8.1Hz),7.22(2H,t,J=8.8Hz),7.31(1H,s),7.37-7.40(2H,m),7.84(2H,d,J=8.3Hz),7.97-8.03(3H,m),9.66(1H,s),13.11-13.38(1H,broad).Example 11

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in N, N-dimethylacetamide 2.5 mL solution at room temperature 86 mg 4- (methanesulfonyl) phenylboronic acid, 69 mg sodium carbonate and polymer supported bis (Acetate) triphenylphosphine palladium (II) 31 mg was added, and the mixture was stirred at 90 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 2.0 mL / L aqueous sodium hydroxide solution (1.0 mL) and ethanol (6.0 mL) were added, and the mixture was stirred at room temperature for 1 hour. 0.5 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography [eluent: 40-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino) -4- ( 28 mg of 4- (methanesulfonyl) phenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.24 (3H, s), 7.11 (1H, d, J = 8.1 Hz), 7.22 (2H, t, J = 8.8 Hz), 7.31 (1H, s) 7.37-7.40 (2H, m), 7.84 (2H, d, J = 8.3Hz), 7.97-8.03 (3H, m), 9.66 (1H, s), 13.11-13.38 (1H, broad).

Examples 12 and 13
In the same manner as in Example 11, the compounds shown in Table 8 were obtained.

2- (4-Fluoroanilino) -4- (4- (methanesulfonamido) phenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.02 (3H, s), 7.02 (1H, dd, J = 8.3, 1.6 Hz), 7.16-7.28 (5H, m), 7.34-7.38 (2H, m ), 7.56 (2H, d, J = 8.8Hz), 7.95 (1H, d, J = 8.3Hz), 9.91 (1H, s).

2- (4-Fluoroanilino) -4- (1H-indol-5-yl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.48 (1H, s), 7.09 (1H, dd, J = 8.3, 1.7 Hz), 7.20-7.26 (2H, m), 7.29-7.31 (2H, m ), 7.36-7.40 (3H, m), 7.45 (1H, d, J = 8.5Hz), 7.76 (1H, s), 7.96 (1H, d, J = 8.3Hz), 9.62 (1H, s), 11.20 (1H, s), 12.87-13.10 (1H, broad).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのトルエン2.0mL、エタノール0.6mLおよび水0.4mL混液に、室温でチオフェン−２−ボロン酸42mg、炭酸ナトリウム64mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）13mgを加え、加圧下で160℃、5分間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび0.5mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン］で精製し、メチル＝２−（４−フルオロアニリノ）−４−（チオフェン−２−イル）ベンゾアートを得た。
得られたメチル＝２−（４−フルオロアニリノ）−４−（チオフェン−２−イル）ベンゾアートのエタノール7.0mL溶液に、2.0mol/L水酸化ナトリウム水溶液1.0mLを加え、室温で1時間30分間攪拌した。反応混合物に0.5mol/L塩酸および酢酸エチルを加え、有機層を分取し、減圧下に溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（チオフェン−２−イル）安息香酸3.5mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.08(1H,dd,J=8.3,1.4Hz),7.13(1H,dd,J=5.0,3.6Hz),7.22-7.27(3H,m),7.34-7.37(2H,m),7.49(1H,d,J=3.6Hz),7.60(1H,d,J=5.0Hz),7.92(1H,d,J=8.3Hz),9.57-9.69(1H,broad).Example 14

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in a mixture of toluene 2.0 mL, ethanol 0.6 mL and water 0.4 mL was mixed at room temperature with thiophene-2-boronic acid 42 mg, sodium carbonate 64 mg and tetrakis (trikis). Phenylphosphine) palladium (0) 13 mg was added, and the mixture was stirred at 160 ° C. for 5 minutes under pressure. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 0.5 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane], and methyl 2- (4-fluoroanilino) -4- (thiophen-2-yl) benzo Got art.
To a 7.0 mL ethanol solution of methyl 2- (4-fluoroanilino) -4- (thiophen-2-yl) benzoate thus obtained, 1.0 mL of a 2.0 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. Stir for 30 minutes. 0.5 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture, the organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 50-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino) -4- ( 3.5 mg of thiophen-2-yl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.08 (1H, dd, J = 8.3, 1.4 Hz), 7.13 (1H, dd, J = 5.0, 3.6 Hz), 7.22-7.27 (3H, m), 7.34-7.37 (2H, m), 7.49 (1H, d, J = 3.6Hz), 7.60 (1H, d, J = 5.0Hz), 7.92 (1H, d, J = 8.3Hz), 9.57-9.69 (1H , broad).

実施例１４と同様にして、以下の化合物を得た。
４−（４−アセチルフェニル）−２−（４−フルオロアニリノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：2.60(3H,s),7.11(1H,dd,J=8.3,1.5Hz),7.21-7.25(2H,m),7.31(1H,d,J=1.5Hz),7.37-7.40(2H,m),7.72(2H,d,J=8.3Hz),8.00-8.03(3H,m),9.59-9.74(1H,broad).Example 15

In the same manner as in Example 14, the following compounds were obtained.
4- (4-Acetylphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.60 (3H, s), 7.11 (1H, dd, J = 8.3, 1.5 Hz), 7.21-7.25 (2H, m), 7.31 (1H, d, J = 1.5Hz), 7.37-7.40 (2H, m), 7.72 (2H, d, J = 8.3Hz), 8.00-8.03 (3H, m), 9.59-9.74 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート80mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、３−シアノフェニルボロン酸48mg、炭酸ナトリウム58mgおよびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）7mgを加え、110℃で19時間攪拌した。反応混合物を室温まで冷却した後、ポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）7mgを加え、110℃で30時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−（３−シアノフェニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（３−シアノフェニル）−２−（４−フルオロアニリノ）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、淡黄色固体の４−（３−シアノフェニル）−２−（４−フルオロアニリノ）安息香酸13mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.11(1H,dd,J=8.3,1.7Hz),7.18-7.26(2H,m),7.31(1H,d,J=1.7Hz),7.36-7.42(2H,m),7.66(1H,dd,J=7.8,7.7Hz),7.86(1H,d,J=7.7Hz),7.91(1H,d,J=7.8Hz),8.00(1H,d,J=8.3Hz),8.09(1H,s),9.66(1H,s),13.10-13.35(1H,broad).Example 16

To a solution of 80 mg of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate in 2.5 mL of N, N-dimethylacetamide, 48 mg of 3-cyanophenylboronic acid, 58 mg of sodium carbonate and polymer-supported di (acetate) 7 mg of dicyclohexylphenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 19 hours. After the reaction mixture was cooled to room temperature, 7 mg of polymer-supported di (acetato) dicyclohexylphenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 30 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 4- (3-cyanophenyl) -2- (4-Fluoroanilino) benzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 4- (3-cyanophenyl) -2- (4-fluoroanilino) benzoate, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue, the solid was collected by filtration, and 4- (3-cyanophenyl) -2- (4-fluoroanilino) benzoic acid was obtained as a pale yellow solid. 13 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.11 (1H, dd, J = 8.3,1.7 Hz), 7.18-7.26 (2H, m), 7.31 (1H, d, J = 1.7 Hz), 7.36 7.42 (2H, m), 7.66 (1H, dd, J = 7.8,7.7Hz), 7.86 (1H, d, J = 7.7Hz), 7.91 (1H, d, J = 7.8Hz), 8.00 (1H, d , J = 8.3Hz), 8.09 (1H, s), 9.66 (1H, s), 13.10-13.35 (1H, broad).

実施例１６と同様にして、以下の化合物を得た。
４−（４−（ｔｅｒｔ−ブチル）フェニル）−２−（４−フルオロアニリノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：1.29(9H,s),7.03(1H,dd,J=8.3,1.2Hz),7.19-7.26(3H,m),7.34-7.40(2H,m),7.44-7.52(4H,m),7.96(1H,d,J=8.3Hz),9.61(1H,s),13.07(1H,s).Example 17

In the same manner as in Example 16, the following compounds were obtained.
4- (4- (tert-butyl) phenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.29 (9H, s), 7.03 (1H, dd, J = 8.3, 1.2 Hz), 7.19-7.26 (3H, m), 7.34-7.40 (2H, m ), 7.44-7.52 (4H, m), 7.96 (1H, d, J = 8.3Hz), 9.61 (1H, s), 13.07 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート80mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、３−クロロフェニルボロン酸51mg、炭酸ナトリウム58mgおよびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）7mgを加え、110℃で19時間攪拌した。反応混合物を室温まで冷却した後、ポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）7mgを加え、110℃で30時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−（３−クロロフェニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（３−クロロフェニル）−２−（４−フルオロアニリノ）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；70-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の４−（３−クロロフェニル）−２−（４−フルオロアニリノ）安息香酸19mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.07(1H,dd,J=8.3,1.7Hz),7.19-7.28(2H,m),7.25(1H,d,J=1.7Hz),7.34-7.42(2H,m),7.43-7.51(2H,m),7.53(1H,dt,J=6.7,1.9Hz),7.63(1H,s),7.98(1H,d,J=8.3Hz),9.64(1H,s),13.05-13.30(1H,broad).Example 18

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 80 mg in N, N-dimethylacetamide 2.5 mL solution, 3-chlorophenylboronic acid 51 mg, sodium carbonate 58 mg and polymer supported di (acetate) dicyclohexyl 7 mg of phenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 19 hours. After the reaction mixture was cooled to room temperature, 7 mg of polymer-supported di (acetato) dicyclohexylphenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 30 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 4- (3-chlorophenyl) -2- ( 4-Fluoroanilino) benzoate was obtained.
To the obtained tert-butyl 4- (3-chlorophenyl) -2- (4-fluoroanilino) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reversed-phase silica gel column chromatography [eluent: 70-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 4- (3 19 mg of -chlorophenyl) -2- (4-fluoroanilino) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.07 (1H, dd, J = 8.3,1.7 Hz), 7.19-7.28 (2H, m), 7.25 (1H, d, J = 1.7 Hz), 7.34 7.42 (2H, m), 7.43-7.51 (2H, m), 7.53 (1H, dt, J = 6.7,1.9Hz), 7.63 (1H, s), 7.98 (1H, d, J = 8.3Hz), 9.64 (1H, s), 13.05-13.30 (1H, broad).

Examples 19-22
In the same manner as in Example 18, the compounds shown in Table 9 were obtained.

2- (4-Fluoroanilino) -4- (2-methylphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.21 (3H, s), 6.73 (1H, dd, J = 8.1, 1.6 Hz), 6.88 (1H, d, J = 1.6 Hz), 7.14-7.35 ( 8H, m), 7.94 (1H, d, J = 8.1Hz), 9.59 (1H, s), 13.00-13.15 (1H, broad).

2- (4-Fluoroanilino) -4- (4-methylphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.33 (3H, s), 7.03 (1H, dd, J = 8.3, 1.7 Hz), 7.19-7.29 (5H, m), 7.33-7.40 (2H, m ), 7.46 (2H, d, J = 8.3Hz), 7.96 (1H, d, J = 8.3Hz), 9.61 (1H, s), 12.90-13.25 (1H, broad).

4- (4-Cyanophenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.11 (1H, dd, J = 8.3,1.6 Hz), 7.18-7.27 (2H, m), 7.29 (1H, d, J = 1.6 Hz), 7.34 7.42 (2H, m), 7.78 (2H, d, J = 8.3Hz), 7.91 (2H, d, J = 8.3Hz), 8.01 (1H, d, J = 8.3Hz), 9.65 (1H, s), 13.00-13.50 (1H, broad).

2- (4-Fluoroanilino) -4- (3-hydroxyphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.78 (1H, dd, J = 8.3, 2.3 Hz), 6.91 (1H, t, J = 1.9 Hz), 6.95-7.02 (2H, m), 7.18- 7.28 (4H, m), 7.32-7.40 (2H, m), 7.95 (1H, d, J = 8.3Hz), 9.56 (1H, s), 9.59 (1H, s), 12.95-13.20 (1H, broad) .

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、２−メトキシ−５−ピリジンボロン酸63mg、炭酸ナトリウム72mgおよびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）8mgを加え、110℃で15時間攪拌した。反応混合物を室温まで冷却した後、２−メトキシ−５−ピリジンボロン酸21mgおよびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）8mgを加え、110℃で36時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−メトキシピリジン−５−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−メトキシピリジン−５−イル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；55-90％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、２−（４−フルオロアニリノ）−４−（２−メトキシピリジン−５−イル）安息香酸トリフルオロ酢酸塩を得た。
２−（４−フルオロアニリノ）−４−（２−メトキシピリジン−５−イル）安息香酸トリフルオロ酢酸塩に、酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.0に調整した。有機層を分取し，水および飽和塩化ナトリウム水溶液で順次洗浄後，無水硫酸マグネシウムで乾燥させ，減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、淡黄色固体の２−（４−フルオロアニリノ）−４−（２−メトキシピリジン−５−イル）安息香酸15mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.88(3H,s),6.89(1H,d,J=8.7Hz),7.05(1H,dd,J=8.3,1.0Hz),7.18-7.26(3H,m),7.34-7.41(2H,m),7.92(1H,dd,J=8.7,2.5Hz),7.97(1H,d,J=8.3Hz),8.41(1H,d,J=2.5Hz),9.66(1H,s),12.90-13.30(1H,broad).Example 23

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.10 g of N, N-dimethylacetamide 2.5 mL solution, 2-methoxy-5-pyridineboronic acid 63 mg, sodium carbonate 72 mg and polymer supported 8 mg of di (acetate) dicyclohexylphenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 15 hours. The reaction mixture was cooled to room temperature, 21 mg of 2-methoxy-5-pyridineboronic acid and 8 mg of polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II) were added, and the mixture was stirred at 110 ° C. for 36 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(2-Methoxypyridin-5-yl) benzoate was obtained.
To the obtained tert-butyl = 2- (4-fluoroanilino) -4- (2-methoxypyridin-5-yl) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 55-90% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino). ) -4- (2-Methoxypyridin-5-yl) benzoic acid trifluoroacetate was obtained.
Ethyl acetate and water were added to 2- (4-fluoroanilino) -4- (2-methoxypyridin-5-yl) benzoic acid trifluoroacetate, and the pH was adjusted to 6.0 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain 15 mg of 2- (4-fluoroanilino) -4- (2-methoxypyridin-5-yl) benzoic acid as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.88 (3H, s), 6.89 (1H, d, J = 8.7 Hz), 7.05 (1H, dd, J = 8.3, 1.0 Hz), 7.18-7.26 ( 3H, m), 7.34-7.41 (2H, m), 7.92 (1H, dd, J = 8.7,2.5Hz), 7.97 (1H, d, J = 8.3Hz), 8.41 (1H, d, J = 2.5Hz ), 9.66 (1H, s), 12.90-13.30 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、３−（アセトアミド）フェニルボロン酸98mg、炭酸ナトリウム72mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）3.2mgを加え、110℃で4時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、ｔｅｒｔ−ブチル＝４−（３−（アセトアミド）フェニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（３−（アセトアミド）フェニル）−２−（４−フルオロアニリノ）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、淡黄色固体の４−（３−（アセトアミド）フェニル）−２−（４−フルオロアニリノ）安息香酸32mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.05(3H,s),6.99(1H,dd,J=8.3,1.7Hz),7.19-7.28(4H,m),7.32-7.41(3H,m),7.61(1H,d,J=8.0Hz),7.77(1H,s),7.98(1H,d,J=8.3Hz),9.62(1H,s),10.02(1H,s),12.95-13.30(1H,broad).Example 24

To a solution of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate (0.10 g) in N, N-dimethylacetamide (2.5 mL) was added 98 mg of 3- (acetamido) phenylboronic acid, 72 mg of sodium carbonate and tetrakis (tri Phenylphosphine) palladium (0) (3.2 mg) was added, and the mixture was stirred at 110 ° C. for 4 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 2: 1], and tert-butyl = 4- (3- (acetamido) phenyl)- 2- (4-Fluoroanilino) benzoate was obtained.
To the obtained tert-butyl 4- (3- (acetamido) phenyl) -2- (4-fluoroanilino) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, methanol was added to the obtained residue, and the solid was collected by filtration to give 4- (3- (acetamido) phenyl) -2- (4-fluoroanilino) as a pale yellow solid. 32 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.05 (3H, s), 6.99 (1H, dd, J = 8.3, 1.7 Hz), 7.19-7.28 (4H, m), 7.32-7.41 (3H, m ), 7.61 (1H, d, J = 8.0Hz), 7.77 (1H, s), 7.98 (1H, d, J = 8.3Hz), 9.62 (1H, s), 10.02 (1H, s), 12.95-13.30 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、４−ヒドロキシフェニルボロン酸75mg、炭酸ナトリウム72mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）3.2mgを加え、110℃で4時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４−ヒドロキシフェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４−ヒドロキシフェニル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；55-90％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（４−ヒドロキシフェニル）安息香酸14mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.82(2H,d,J=8.3Hz),6.98(1H,dd,J=8.3,1.2Hz),7.18-7.27(3H,m),7.32-7.38(2H,m),7.41(2H,d,J=8.3Hz),7.92(1H,d,J=8.3Hz),9.60(1H,s),9.68(1H,s),12.85-13.10(1H,broad).Example 25

To a solution of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate (0.10 g) in N, N-dimethylacetamide (2.5 mL) was added 4-hydroxyphenylboronic acid (75 mg), sodium carbonate (72 mg) and tetrakis (triphenylphosphine). ) Palladium (0) 3.2 mg was added and stirred at 110 ° C. for 4 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(4-Hydroxyphenyl) benzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2- (4-fluoroanilino) -4- (4-hydroxyphenyl) benzoate, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 55-90% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4 -Fluoroanilino) -4- (4-hydroxyphenyl) benzoic acid 14 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.82 (2H, d, J = 8.3 Hz), 6.98 (1H, dd, J = 8.3, 1.2 Hz), 7.18-7.27 (3H, m), 7.32 7.38 (2H, m), 7.41 (2H, d, J = 8.3Hz), 7.92 (1H, d, J = 8.3Hz), 9.60 (1H, s), 9.68 (1H, s), 12.85-13.10 (1H , broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.20gのトルエン4.0mL、エタノール1.2mLおよび水0.6mL混液に、４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）イソキノリン0.17g、炭酸水素ナトリウム0.12gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）35mgを加え、窒素雰囲気下、4時間加熱還流した。反応混合物を室温まで冷却した後、テトラキス（トリフェニルホスフィン）パラジウム（０）35mgを加え、窒素雰囲気下、4時間加熱還流した。反応混合物を室温まで冷却した後、水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、淡赤色固体のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（イソキノリン−４−イル）ベンゾアート0.11gを得た。
¹H-NMR(DMSO-d₆)δ値：1.61(9H,s),6.96(1H,dd,J=8.1,1.2Hz),7.11(1H,d,J=1.2Hz),7.17(2H,t,J=8.8Hz),7.36-7.40(2H,m),7.74(1H,t,J=7.5Hz),7.82(1H,t,J=7.5Hz),7.88(1H,d,J=8.0Hz),8.02(1H,d,J=8.0Hz),8.21(1H,d,J=8.3Hz),8.43(1H,s),9.34(1H,s),9.42(1H,s).Example 26

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.20 g of toluene 4.0 mL, ethanol 1.2 mL and water 0.6 mL were mixed with 4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) isoquinoline 0.17 g, sodium hydrogen carbonate 0.12 g and tetrakis (triphenylphosphine) palladium (0) 35 mg were added, and the mixture was heated to reflux for 4 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 35 mg of tetrakis (triphenylphosphine) palladium (0) was added, and the mixture was heated to reflux for 4 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 2: 1] to give tert-butyl = 2- (4-fluoroanilino) -4- (isoquinoline- 0.11 g of 4-yl) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.61 (9H, s), 6.96 (1H, dd, J = 8.1, 1.2 Hz), 7.11 (1H, d, J = 1.2 Hz), 7.17 (2H, t, J = 8.8Hz), 7.36-7.40 (2H, m), 7.74 (1H, t, J = 7.5Hz), 7.82 (1H, t, J = 7.5Hz), 7.88 (1H, d, J = 8.0 Hz), 8.02 (1H, d, J = 8.0Hz), 8.21 (1H, d, J = 8.3Hz), 8.43 (1H, s), 9.34 (1H, s), 9.42 (1H, s).

実施例２６と同様にして、以下の化合物を得た。
ｔｅｒｔ−ブチル＝４−（ベンゾチオフェン−２−イル）−２−（４−フルオロアニリノ）ベンゾアート
¹H-NMR(CDCl₃)δ値：1.63(9H,s),7.05(1H,dd,J=8.4,1.8Hz),7.07-7.13(2H,m),7.24-7.37(4H,m),7.40(1H,d,J=1.8Hz),7.50(1H,s),7.73-7.81(2H,m),7.95(1H,d,J=8.4Hz),9.54(1H,s).Example 27

In the same manner as in Example 26, the following compound was obtained.
tert-Butyl 4- (Benzothiophen-2-yl) -2- (4-fluoroanilino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 7.05 (1H, dd, J = 8.4, 1.8 Hz), 7.07-7.13 (2H, m), 7.24-7.37 (4H, m), 7.40 (1H, d, J = 1.8Hz), 7.50 (1H, s), 7.73-7.81 (2H, m), 7.95 (1H, d, J = 8.4Hz), 9.54 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（イソキノリン−４−イル）ベンゾアート110mgのトリフルオロ酢酸3.0mL溶液を室温で1時間攪拌した。反応混合物に、水および酢酸エチルを加え、1.0mol/L水酸化ナトリウム水溶液でpH6.0に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンおよびジイソプロピルエーテルを加え、固形物をろ取し、淡緑色固体の２−（４−フルオロアニリノ）−４−（イソキノリン−４−イル）安息香酸50mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.95(1H,dd,J=8.0,1.5Hz),7.11(1H,d,J=1.5Hz),7.17(2H,t,J=8.7Hz),7.37-7.40(2H,m),7.74(1H,t,J=7.4Hz),7.83(1H,t,J=7.4Hz),7.90(1H,d,J=8.6Hz),8.07(1H,d,J=8.3Hz),8.22(1H,d,J=7.6Hz),8.44(1H,s),9.35(1H,s),9.67(1H,s),13.20-13.26(1H,broad).Example 28

A solution of tert-butyl 2- (4-fluoroanilino) -4- (isoquinolin-4-yl) benzoate (110 mg) in trifluoroacetic acid (3.0 mL) was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 6.0 with 1.0 mol / L sodium hydroxide aqueous solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the solid was collected by filtration to obtain 50 mg of 2- (4-fluoroanilino) -4- (isoquinolin-4-yl) benzoic acid as a pale green solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.95 (1H, dd, J = 8.0, 1.5 Hz), 7.11 (1H, d, J = 1.5 Hz), 7.17 (2H, t, J = 8.7 Hz) , 7.37-7.40 (2H, m), 7.74 (1H, t, J = 7.4Hz), 7.83 (1H, t, J = 7.4Hz), 7.90 (1H, d, J = 8.6Hz), 8.07 (1H, d, J = 8.3Hz), 8.22 (1H, d, J = 7.6Hz), 8.44 (1H, s), 9.35 (1H, s), 9.67 (1H, s), 13.20-13.26 (1H, broad).

実施例２８と同様にして、以下の化合物を得た。
４−（ベンゾチオフェン−２−イル）−２−（４−フルオロアニリノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：7.22(1H,d,J=8.3Hz),7.24-7.32(2H,m),7.33-7.44(5H,m),7.84-7.90(2H,m),7.95-8.02(2H,m),9.64(1H,s),13.05-13.35(1H,broad).Example 29

In the same manner as in Example 28, the following compound was obtained.
4- (Benzothiophen-2-yl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.22 (1H, d, J = 8.3 Hz), 7.24-7.32 (2H, m), 7.33-7.44 (5H, m), 7.84-7.90 (2H, m ), 7.95-8.02 (2H, m), 9.64 (1H, s), 13.05-13.35 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.20gのＮ，Ｎ−ジメチルホルムアミド1mL溶液に、酢酸カリウム0.16g、テトラブチルアンモニウムクロリド0.15g、シクロペンテン0.24mL、酢酸パラジウム3.1mgおよびトリフェニルホスフィン3.6mgを加え、窒素雰囲気下、室温で17時間攪拌した
。反応混合物に酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：トルエン＝５：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝４−（２−シクロペンテン−１−イル）−２−（４−フルオロアニリノ）ベンゾアート73mgを得た。
¹H-NMR(CDCl₃)δ値：1.59(9H,s),1.61-1.72(1H,m),2.28-2.48(3H,m),3.70-3.80(1H,m),5.66-5.70(1H,m),5.88-5.92(1H,m),6.54(1H,dd,J=8.3,1.6Hz),6.92(1H,d,J=1.6Hz),6.99-7.06(2H,m),7.16-7.22(2H,m),7.83(1H,d,J=8.3Hz),9.44(1H,s).Example 30

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.20 g in N, N-dimethylformamide 1 mL solution, potassium acetate 0.16 g, tetrabutylammonium chloride 0.15 g, cyclopentene 0.24 mL, palladium acetate 3.1 mg and triphenylphosphine 3.6 mg were added, and the mixture was stirred at room temperature for 17 hours under a nitrogen atmosphere. Ethyl acetate and 10% aqueous citric acid solution were added to the reaction mixture. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: toluene = 5: 1], and tert-butyl 4- (2-cyclopenten-1-yl) -2- (4 -Fluoroanilino) benzoate 73 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.59 (9H, s), 1.61-1.72 (1H, m), 2.28-2.48 (3H, m), 3.70-3.80 (1H, m), 5.66-5.70 (1H , m), 5.88-5.92 (1H, m), 6.54 (1H, dd, J = 8.3,1.6Hz), 6.92 (1H, d, J = 1.6Hz), 6.99-7.06 (2H, m), 7.16- 7.22 (2H, m), 7.83 (1H, d, J = 8.3Hz), 9.44 (1H, s).

ｔｅｒｔ−ブチル＝４−（２−シクロペンテン−１−イル）−２−（４−フルオロアニリノ）ベンゾアート27mgに、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、白色固体の４−（２−シクロペンテン−１−イル）−２−（４−フルオロアニリノ）安息香酸22mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.52-1.65(1H,m),2.24-2.44(3H,m),3.73-3.83(1H,m),5.66-5.76(1H,m),5.88-5.96(1H,m),6.58(1H,dd,J=8.3,1.5Hz),6.90(1H,d,J=1.5Hz),7.16-7.31(4H,m),7.82(1H,d,J=8.3Hz),9.55(1H,s),12.75-13.05(1H,broad).Example 31

10 mL of trifluoroacetic acid was added to 27 mg of tert-butyl 4- (2-cyclopenten-1-yl) -2- (4-fluoroanilino) benzoate, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue, the solid was collected by filtration, and white solid 4- (2-cyclopenten-1-yl) -2- (4-fluoroanilino) 22 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52-1.65 (1H, m), 2.24-2.44 (3H, m), 3.73-3.83 (1H, m), 5.66-5.76 (1H, m), 5.88 -5.96 (1H, m), 6.58 (1H, dd, J = 8.3,1.5Hz), 6.90 (1H, d, J = 1.5Hz), 7.16-7.31 (4H, m), 7.82 (1H, d, J = 8.3Hz), 9.55 (1H, s), 12.75-13.05 (1H, broad).

ｔｅｒｔ−ブチル＝４−（２−シクロペンテン−１−イル）−２−（４−フルオロアニリノ）ベンゾアート45mgのメタノール2.0mL溶液に、5％パラジウム−炭素9mgを加え、水素雰囲気下、室温で6時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物に、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、白色固体の４−シクロペンチル−２−（４−フルオロアニリノ）安息香酸24mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.38-1.52(2H,m),1.54-1.76(4H,m),1.89-2.00(2H,m),2.82-2.93(1H,m),6.67(1H,dd,J=8.3,1.5Hz),6.94(1H,d,J=1.5Hz),7.16-7.32(4H,m),7.81(1H,d,J=8.3Hz),9.53(1H,s),12.87(1H,s).Example 32

tert-Butyl 4- (2-cyclopenten-1-yl) -2- (4-fluoroanilino) benzoate 45 mg in methanol 2.0 mL solution was added 5% palladium-carbon 9 mg, and at room temperature under hydrogen atmosphere. Stir for 6 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue, and the solid was collected by filtration to obtain 24 mg of 4-cyclopentyl-2- (4-fluoroanilino) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.38-1.52 (2H, m), 1.54-1.76 (4H, m), 1.89-2.00 (2H, m), 2.82-2.93 (1H, m), 6.67 (1H, dd, J = 8.3,1.5Hz), 6.94 (1H, d, J = 1.5Hz), 7.16-7.32 (4H, m), 7.81 (1H, d, J = 8.3Hz), 9.53 (1H, s), 12.87 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−ヒドロキシベンゾアート0.30gのＮ，Ｎ−ジメチルホルムアミド3.0mL溶液に、室温で炭酸カリウム0.16gおよびシクロヘキシルブロミド0.42mLを加え、80℃で8時間攪拌した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝８：１］で精製し、無色油状物のメチル＝４−（シクロヘキシルオキシ）−２−（４−フルオロアニリノ）ベンゾアート40mgを得た。
¹H-NMR(CDCl₃)δ値：1.22-1.38(3H,m),1.41-1.64(3H,m),1.70-1.82(2H,m),1.86-1.99(2H,m),3.86(3H,s),4.15-4.20(1H,m),6.27(1H,dd,J=8.9,2.4Hz),6.48(1H,d,J=2.4Hz),7.02-7.07(2H,m),7.18-7.22(2H,m),7.88(1H,d,J=8.9Hz),9.44(1H,s).Example 33

To a solution of 0.30 g of methyl 2- (4-fluoroanilino) -4-hydroxybenzoate in 3.0 mL of N, N-dimethylformamide was added 0.16 g of potassium carbonate and 0.42 mL of cyclohexyl bromide at room temperature, and the mixture was heated at 80 ° C. for 8 hours. Stir. After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Co., Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 8: 1] to give colorless oily methyl 4- (cyclohexyloxy) 40 mg of -2- (4-fluoroanilino) benzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.22-1.38 (3H, m), 1.41-1.64 (3H, m), 1.70-1.82 (2H, m), 1.86-1.99 (2H, m), 3.86 (3H , s), 4.15-4.20 (1H, m), 6.27 (1H, dd, J = 8.9,2.4Hz), 6.48 (1H, d, J = 2.4Hz), 7.02-7.07 (2H, m), 7.18- 7.22 (2H, m), 7.88 (1H, d, J = 8.9Hz), 9.44 (1H, s).

メチル＝４−（シクロヘキシルオキシ）−２−（４−フルオロアニリノ）ベンゾアート40mgの２−プロパノール2.0mL懸濁液に、室温で10％水酸化ナトリウム水溶液0.25mLを加え、5時間加熱還流した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の４−（シクロヘキシルオキシ）−２−（４−フルオロアニリノ）安息香酸8mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.17-1.54(6H,m),1.62-1.71(2H,m),1.83-1.91(2H,m),4.25-4.29(1H,m),6.37(1H,dd,J=8.9,2.3Hz),6.40(1H,d,J=2.3Hz),7.18-7.25(2H,m),7.26-7.30(2H,m),7.81(1H,d,J=8.9Hz),9.57-9.66(1H,broad).Example 34

Methyl 4- (cyclohexyloxy) -2- (4-fluoroanilino) benzoate 40 mg of 2-propanol 2.0 mL suspension was added 10% aqueous sodium hydroxide solution 0.25 mL at room temperature, and heated to reflux for 5 hours. . After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to obtain 8 mg of 4- (cyclohexyloxy) -2- (4-fluoroanilino) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.17-1.54 (6H, m), 1.62-1.71 (2H, m), 1.83-1.91 (2H, m), 4.25-4.29 (1H, m), 6.37 (1H, dd, J = 8.9,2.3Hz), 6.40 (1H, d, J = 2.3Hz), 7.18-7.25 (2H, m), 7.26-7.30 (2H, m), 7.81 (1H, d, J = 8.9Hz), 9.57-9.66 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.50gのトルエン7.5mL溶液に、室温で１−フルオロ−４−ヨードベンゼン0.22mL、炭酸セシウム1.3g、酢酸パラジウム4.3mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル12mgを加え、4時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム4.3mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル12mgを加え、13時間加熱還流した。反応混合物を室温まで冷却した後、水および酢酸エチルを加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、褐色油状物のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−フェニルベンゾアート0.44gを得た。
¹H-NMR(CDCl₃)δ値：1.63(9H,s),6.93(1H,dd,J=8.3,1.9Hz),7.03-7.07(2H,m),7.24-7.28(3H,m),7.32-7.43(3H,m),7.48-7.52(2H,m),7.97(1H,d,J=8.3Hz),9.52(1H,s).Example 35

To a solution of 0.50 g of tert-butyl-2-amino-4-phenylbenzoate in 7.5 mL of toluene at room temperature, 0.22 mL of 1-fluoro-4-iodobenzene, 1.3 g of cesium carbonate, 4.3 mg of palladium acetate and rac-2,2 '-Bis (diphenylphosphino) -1,1'-binaphthyl (12 mg) was added, and the mixture was heated to reflux for 4 hours. After the reaction mixture was cooled to room temperature, 4.3 mg of palladium acetate and 12 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl were added, and the mixture was heated to reflux for 13 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl 2- (4-fluoroanisate) as a brown oily substance. 0.44 g of reno) -4-phenylbenzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 6.93 (1H, dd, J = 8.3, 1.9 Hz), 7.03-7.07 (2H, m), 7.24-7.28 (3H, m), 7.32-7.43 (3H, m), 7.48-7.52 (2H, m), 7.97 (1H, d, J = 8.3Hz), 9.52 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート1.0gのトルエン10mL溶液に、室温で１−フルオロ−４−ヨードベンゼン0.98mL、炭酸セシウム2.2g、酢酸パラジウム8mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル21mgを加え、窒素雰囲気下、6時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム8mgおよびｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル21mgを加え、窒素雰囲気下、10時間加熱還流した。反応混合物を室温まで冷却した後、水を加え、不溶物をろ去した。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、淡黄色油状物のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−フェネチルベンゾアート0.80gを得た。
¹H-NMR(DMSO-d₆)δ値：1.55(9H,s),2.78-2.84(4H,m),6.67(1H,dd,J=8.3,1.5Hz),6.77(1H,d,J=1.5Hz),7.04-7.22(7H,m),7.25-7.29(2H,m),7.75(1H,d,J=8.3Hz),9.25(1H,s).Example 36

To a 10 mL toluene solution of 1.0 g of tert-butyl = 2-amino-4-phenethylbenzoate at room temperature, 0.98 mL of 1-fluoro-4-iodobenzene, 2.2 g of cesium carbonate, 8 mg of palladium acetate and rac-2,2′- Bis (diphenylphosphino) -1,1′-binaphthyl (21 mg) was added, and the mixture was heated to reflux for 6 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 8 mg of palladium acetate and 21 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl were added, and the mixture was heated to reflux for 10 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1], and tert-butyl = 2- (4-fluoroanilino) -4-phenethylbenzo was obtained as a pale yellow oil. Obtained 0.80 g of art.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.55 (9H, s), 2.78-2.84 (4H, m), 6.67 (1H, dd, J = 8.3, 1.5 Hz), 6.77 (1H, d, J = 1.5Hz), 7.04-7.22 (7H, m), 7.25-7.29 (2H, m), 7.75 (1H, d, J = 8.3Hz), 9.25 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−フェニルベンゾアート0.44gのトリフルオロ酢酸9.0mL溶液を室温で1時間攪拌した。反応混合物の溶媒を減圧下で留去し、酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH5.0に調整した。有機層を分取し、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、淡黄色固体の２−（４−フルオロアニリノ）−４−フェニル安息香酸0.11gを得た。
¹H-NMR(DMSO-d₆)δ値：7.05(1H,dd,J=8.1,1.8Hz),7.20-7.25(2H,m),7.26(1H,d,J=1.8Hz),7.36-7.47(5H,m),7.56-7.58(2H,m),7.98(1H,d,J=8.1Hz),9.63(1H,s),13.08-13.14(1H,broad).Example 37

A solution of 0.44 g of tert-butyl = 2- (4-fluoroanilino) -4-phenylbenzoate in 9.0 mL of trifluoroacetic acid was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 5.0 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 0.11 g of 2- (4-fluoroanilino) -4-phenylbenzoic acid as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.05 (1H, dd, J = 8.1,1.8Hz), 7.20-7.25 (2H, m), 7.26 (1H, d, J = 1.8Hz), 7.36 7.47 (5H, m), 7.56-7.58 (2H, m), 7.98 (1H, d, J = 8.1Hz), 9.63 (1H, s), 13.08-13.14 (1H, broad).

実施例３７と同様にして、以下の化合物を得た。
２−（４−フルオロアニリノ）−４−フェネチル安息香酸
¹H-NMR(DMSO-d₆)δ値：2.77-2.86(4H,m),6.67(1H,dd,J=8.3,1.3Hz),6.79(1H,d,J=1.3Hz),7.06-7.22(7H,m),7.25-7.29(2H,m),7.80(1H,d,J=8.3Hz),9.51(1H,s),12.88-12.93(1H,broad).Example 38

In the same manner as in Example 37, the following compound was obtained.
2- (4-Fluoroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.77-2.86 (4H, m), 6.67 (1H, dd, J = 8.3,1.3Hz), 6.79 (1H, d, J = 1.3Hz), 7.06- 7.22 (7H, m), 7.25-7.29 (2H, m), 7.80 (1H, d, J = 8.3Hz), 9.51 (1H, s), 12.88-12.93 (1H, broad).

Ｎ−（５−ベンゾイル−２−メチルフェニル）−Ｎ−（４−フルオロフェニル）アセトアミド0.52gのピリジン5.0mLおよび水5.0mL混液に、室温で過マンガン酸カリウム0.24gを加え、30分間加熱還流した。反応混合物を室温まで冷却した後、過マンガン酸カリウム0.24gを加え、30分間加熱還流した。反応混合物を室温まで冷却した後、過マンガン酸カリウム0.24gを加え、30分間加熱還流した。反応混合物を室温まで冷却した後、さらに過マンガン酸カリウム0.24gを加え、30分間加熱還流した。反応混合物を冷却した後、酢酸エチルを加え、6.0mol/L塩酸でpH2.3に調整し、不溶物をろ去した。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝１：２］で精製し、白色固体の４−ベンゾイル−２−（Ｎ−（４−フルオロフェニル）アセトアミド）安息香酸0.39gを得た。
¹H-NMR(DMSO-d₆)δ値：1.92(3H,s),7.15-7.19(1H,m),7.31(2H,t,J=8.4Hz),7.47-7.82(8H,m),7.93(1H,t,J=8.8Hz),13.33-13.39(1H,broad).Example 39

N- (5-benzoyl-2-methylphenyl) -N- (4-fluorophenyl) acetamide 0.52 g of pyridine (5.0 mL) and water (5.0 mL) were mixed with potassium permanganate (0.24 g) at room temperature, and heated under reflux for 30 minutes. did. The reaction mixture was cooled to room temperature, 0.24 g of potassium permanganate was added, and the mixture was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, 0.24 g of potassium permanganate was added, and the mixture was heated to reflux for 30 minutes. After the reaction mixture was cooled to room temperature, 0.24 g of potassium permanganate was further added, and the mixture was heated to reflux for 30 minutes. After the reaction mixture was cooled, ethyl acetate was added, the pH was adjusted to 2.3 with 6.0 mol / L hydrochloric acid, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 1: 2] to give 4-benzoyl-2- (N- (4-fluorophenyl) acetamido) benzoic acid 0.39 as a white solid. g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.92 (3H, s), 7.15-7.19 (1H, m), 7.31 (2H, t, J = 8.4 Hz), 7.47-7.82 (8H, m), 7.93 (1H, t, J = 8.8Hz), 13.33-13.39 (1H, broad).

４−ベンゾイル−２−（Ｎ−（４−フルオロフェニル）アセトアミド）安息香酸0.39gのジオキサン2.0mL溶液に、6.0mol/L塩酸2.0mLを加え、2時間30分間加熱還流した。反応混合物を室温まで冷却した後、6.0mol/L塩酸1.0mLを加え、4時間加熱還流した。反応混合物を室温まで冷却した後、減圧下で溶媒を留去し、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；クロロホルム：メタノール：酢酸＝２０：１：１］で精製し、黄色固体の４−ベンゾイル−２−（４−フルオロアニリノ）安息香酸0.27gを得た。
¹H-NMR(DMSO-d₆)δ値：7.06(1H,d,J=8.1Hz),7.18-7.22(2H,m),7.30(1H,s),7.34-7.37(2H,m),7.56(2H,t,J=7.6Hz),7.67(1H,t,J=7.6Hz),7.75(2H,d,J=7.6Hz),8.04(1H,d,J=8.1Hz),9.56(1H,s),13.42-13.52(1H,broad).Example 40

To a solution of 0.39 g of 4-benzoyl-2- (N- (4-fluorophenyl) acetamido) benzoic acid in 2.0 mL of dioxane was added 2.0 mL of 6.0 mol / L hydrochloric acid, and the mixture was heated to reflux for 2 hours and 30 minutes. After cooling the reaction mixture to room temperature, 6.0 mL of 6.0 mol / L hydrochloric acid was added, and the mixture was heated to reflux for 4 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: chloroform: methanol: acetic acid = 20: 1: 1] and 0.27 g of 4-benzoyl-2- (4-fluoroanilino) benzoic acid as a yellow solid. Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.06 (1H, d, J = 8.1 Hz), 7.18-7.22 (2H, m), 7.30 (1H, s), 7.34-7.37 (2H, m), 7.56 (2H, t, J = 7.6Hz), 7.67 (1H, t, J = 7.6Hz), 7.75 (2H, d, J = 7.6Hz), 8.04 (1H, d, J = 8.1Hz), 9.56 ( 1H, s), 13.42-13.52 (1H, broad).

４−ベンゾイル−２−（４−フルオロアニリノ）安息香酸0.13gのメタノール1.3mLおよび酢酸エチル1.3mL混液に、5％パラジウム−炭素26mgを加え、水素雰囲気下、室温で6時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物にヘキサンおよびジイソプロピルエーテルを加え、固形物をろ取し、白色固体の４−ベンジル−２−（４−フルオロアニリノ）安息香酸85mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.86(2H,s),6.60(1H,d,J=8.1Hz),6.95(1H,s),7.14-7.24(7H,m),7.28(2H,t,J=7.5Hz),7.80(1H,d,J=8.1Hz).Example 41

To a mixed solution of methanol (1.3 mL) of 4-benzoyl-2- (4-fluoroanilino) benzoic acid (0.13 g) and ethyl acetate (1.3 mL) was added 26% of 5% palladium-carbon, and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the solid was collected by filtration to obtain 85 mg of 4-benzyl-2- (4-fluoroanilino) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.86 (2H, s), 6.60 (1H, d, J = 8.1 Hz), 6.95 (1H, s), 7.14-7.24 (7H, m), 7.28 ( 2H, t, J = 7.5Hz), 7.80 (1H, d, J = 8.1Hz).

２−ヨード−４−フェノキシ安息香酸45mgのＮ，Ｎ−ジメチルホルムアミド0.9mL溶液に、４−クロロアニリン27mg、銅粉5mgおよびＮ−メチルモルホリン0.036mLを加え、加圧下、180℃で15分間攪拌した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；65-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（４−クロロアニリノ）−４−フェノキシ安息香酸9mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.37(1H,dd,J=8.9,2.4Hz),6.64(1H,d,J=2.4Hz),7.12-7.14(2H,m),7.20-7.25(3H,m),7.32-7.36(2H,m),7.41-7.46(2H,m),7.91(1H,d,J=8.9Hz),9.77(1H,s),12.84-13.18(1H,broad).Example 42

To a solution of 45 mg of 2-iodo-4-phenoxybenzoic acid in 0.9 mL of N, N-dimethylformamide, add 27 mg of 4-chloroaniline, 5 mg of copper powder and 0.036 mL of N-methylmorpholine, and stir at 180 ° C. for 15 minutes under pressure. did. After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography [eluent: 65-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution], and white solid 2- (4-chloroanilino) -4-phenoxybenzoic acid 9 mg Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.37 (1H, dd, J = 8.9, 2.4 Hz), 6.64 (1H, d, J = 2.4 Hz), 7.12-7.14 (2H, m), 7.20- 7.25 (3H, m), 7.32-7.36 (2H, m), 7.41-7.46 (2H, m), 7.91 (1H, d, J = 8.9Hz), 9.77 (1H, s), 12.84-13.18 (1H, broad).

Examples 43-47
In the same manner as in Example 42, the compounds shown in Table 10 were obtained.

2-((Benzo-1,3-dioxol-5-yl) amino) -4-phenoxybenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.00 (2H, s), 6.25 (1H, dd, J = 8.8, 2.4 Hz), 6.45 (1H, d, J = 2.4 Hz), 6.67 (1H, dd, J = 8.3,2.2Hz), 6.84 (1H, d, J = 2.2Hz), 6.86 (1H, d, J = 8.3Hz), 7.08-7.10 (2H, m), 7.19 (1H, t, J = 7.4Hz), 7.38-7.43 (2H, m), 7.86 (1H, d, J = 8.8Hz), 9.49-9.67 (1H, broad).

2- (4-Isopropylanilino) -4-phenoxybenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.18 (6H, d, J = 6.8 Hz), 2.79-2.90 (1H, m), 6.29 (1H, dd, J = 8.8,2.3 Hz), 6.58 ( 1H, d, J = 2.3Hz), 7.09-7.13 (4H, m), 7.17-7.21 (3H, m), 7.39-7.44 (2H, m), 7.89 (1H, d, J = 8.8Hz), 9.71 (1H, s), 12.75-13.03 (1H, broad).

2- (2,4-Dimethoxyanilino) -4-phenoxybenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.74 (3H, s), 3.75 (3H, s), 6.23 (1H, dd, J = 8.8, 2.3 Hz), 6.26 (1H, d, J = 2.3 Hz), 6.47 (1H, dd, J = 8.7,2.7Hz), 6.63 (1H, d, J = 2.7Hz), 7.06 (2H, d, J = 7.8Hz), 7.14 (1H, d, J = 8.8 Hz), 7.18 (1H, t, J = 7.4Hz), 7.38-7.42 (2H, m), 7.85 (1H, d, J = 8.7Hz), 9.37 (1H, s).

2-anilino-4-phenoxybenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.34 (1H, dd, J = 8.9,2.3 Hz), 6.64 (1H, d, J = 2.3 Hz), 7.05 (1H, t, J = 7.5 Hz) , 7.11-7.13 (2H, m), 7.18-7.22 (3H, m), 7.31 (2H, t, J = 7.7Hz), 7.42 (2H, t, J = 7.8Hz), 7.91 (1H, d, J = 8.9Hz), 9.78 (1H, s), 12.82-13.07 (1H, broad).

2- (4-Methoxy-2-methylanilino) -4-phenoxybenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.13 (3H, s), 3.73 (3H, s), 6.03 (1H, d, J = 2.3 Hz), 6.19 (1H, dd, J = 8.8, 2.3 Hz), 6.75 (1H, dd, J = 8.6,2.8Hz), 6.87 (1H, d, J = 2.8Hz), 7.04 (2H, d, J = 7.7Hz), 7.12 (1H, d, J = 8.6 Hz), 7.17 (1H, t, J = 7.7Hz), 7.38 (2H, t, J = 7.7Hz), 7.86 (1H, d, J = 8.8Hz), 9.39 (1H, s), 12.63-12.95 ( 1H, broad).

２−ヨード−４−フェノキシ安息香酸40mgのＮ，Ｎ−ジメチルホルムアミド1.0mL溶液に、シクロヘキシルアミン0.027mL、ヨウ化銅（I）3mg、銅粉3mgおよびＮ−メチルモルホリン0.040mLを加え、加圧下、180℃で15分間攪拌した。反応混合物を室温まで冷却した後、10%クエン酸水溶液および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル：酢酸＝２０：１０：１］で精製し、白色固体の２−（シクロヘキシルアミノ）−４−フェノキシ安息香酸5mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.14-1.38(5H,m),1.48-1.57(1H,m),1.59-1.67(2H,m),1.81-1.91(2H,m),3.20-3.40(1H,broad),6.04(1H,dd,J=9.0,2.0Hz),6.25(1H,d,J=2.0Hz),7.09(2H,d,J=7.7Hz),7.21(1H,t,J=7.7Hz),7.43(2H,t,J=7.7Hz),7.76(1H,d,J=9.0Hz),7.95-8.06(1H,broad),12.35-12.49(1H,broad).Example 48

To a 1.0 mL N, N-dimethylformamide solution of 40 mg of 2-iodo-4-phenoxybenzoic acid, 0.027 mL of cyclohexylamine, 3 mg of copper (I) iodide, 3 mg of copper powder and 0.040 mL of N-methylmorpholine are added under pressure. And stirred at 180 ° C. for 15 minutes. After the reaction mixture was cooled to room temperature, 10% aqueous citric acid solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate: acetic acid = 20: 10: 1], and white solid 2- (cyclohexylamino) -4 -5 mg of phenoxybenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.14-1.38 (5H, m), 1.48-1.57 (1H, m), 1.59-1.67 (2H, m), 1.81-1.91 (2H, m), 3.20 -3.40 (1H, broad), 6.04 (1H, dd, J = 9.0,2.0Hz), 6.25 (1H, d, J = 2.0Hz), 7.09 (2H, d, J = 7.7Hz), 7.21 (1H, t, J = 7.7Hz), 7.43 (2H, t, J = 7.7Hz), 7.76 (1H, d, J = 9.0Hz), 7.95-8.06 (1H, broad), 12.35-12.49 (1H, broad).

実施例４８と同様にして以下の化合物を得た。
２−（４−フルオロベンジルアミノ）−４−フェノキシ安息香酸
¹H-NMR(DMSO-d₆)δ値：4.34(2H,s),6.09-6.12(2H,m),6.98(2H,d,J=8.0Hz),7.11-7.28(5H,m),7.38(2H,t,J=7.7Hz),7.79(1H,d,J=8.6Hz),8.38-8.48(1H,broad),12.48-12.60(1H,broad).Example 49

In the same manner as in Example 48, the following compound was obtained.
2- (4-Fluorobenzylamino) -4-phenoxybenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 4.34 (2H, s), 6.09-6.12 (2H, m), 6.98 (2H, d, J = 8.0 Hz), 7.11-7.28 (5H, m), 7.38 (2H, t, J = 7.7Hz), 7.79 (1H, d, J = 8.6Hz), 8.38-8.48 (1H, broad), 12.48-12.60 (1H, broad).

２−ヨード−４−フェノキシ安息香酸0.88gのＮ，Ｎ−ジメチルホルムアミド8.8mL溶液に、キノリン−８−アミン0.75g、Ｎ−メチルモルホリン0.85mL、ヨウ化銅（I）0.15gおよび銅粉49mgを加え、90℃で6時間30分間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加え、10％クエン酸水溶液でpH6.5に調整し、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２：１］で精製することにより、淡黄色固体の４−フェノキシ−２−（キノリン−８−イルアミノ）安息香酸0.15gを得た。
¹H-NMR(DMSO-d₆)δ値：6.49(1H,dd,J=8.8,2.2Hz),7.16-7.20(3H,m),7.23(1H,t,J=7.3Hz),7.42-7.51(4H,m),7.59-7.63(2H,m),8.00(1H,d,J=8.8Hz),8.35(1H,dd,J=8.3,1.5Hz),8.89(1H,dd,J=4.2,1.7Hz),11.07(1H,s),12.89-12.96(1H,broad).Example 50

To a solution of 0.88 g of 2-iodo-4-phenoxybenzoic acid in 8.8 mL of N, N-dimethylformamide, 0.75 g of quinolin-8-amine, 0.85 mL of N-methylmorpholine, 0.15 g of copper (I) iodide and 49 mg of copper powder And stirred at 90 ° C. for 6 hours and 30 minutes. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, the pH was adjusted to 6.5 with 10% aqueous citric acid solution, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 2: 1] to give 0.15 g of 4-phenoxy-2- (quinolin-8-ylamino) benzoic acid as a pale yellow solid. Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.49 (1H, dd, J = 8.8, 2.2 Hz), 7.16-7.20 (3H, m), 7.23 (1H, t, J = 7.3 Hz), 7.42 7.51 (4H, m), 7.59-7.63 (2H, m), 8.00 (1H, d, J = 8.8Hz), 8.35 (1H, dd, J = 8.3,1.5Hz), 8.89 (1H, dd, J = 4.2, 1.7Hz), 11.07 (1H, s), 12.89-12.96 (1H, broad).

２−（アセトアミド）−４−フェノキシ安息香酸0.10gのＮ，Ｎ−ジメチルホルムアミド2.0mL溶液に、室温で60%水素化ナトリウム30mgを加え、同温度で30分間攪拌した。反応混合物に、室温でベンジルブロミド0.092mLを加え、同温度で2時間30分間攪拌した。反応混合物に、室温で60%水素化ナトリウム15mgを加え、同温度で30分間攪拌した。反応混合物に、室温でベンジルブロミド0.022mLを加え、同温度で1時間30分間攪拌した。反応混合物に、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル：酢酸＝４０：１０：１］で精製し、無色油状物の２−（Ｎ−ベンジルアセトアミド）−４−フェノキシ安息香酸0.10gを得た。
¹H-NMR(DMSO-d₆)δ値：1.72(3H,s),3.93(1H,d,J=14.8Hz),5.42(1H,d,J=14.8Hz),6.42(1H,d,J=2.5Hz),6.90(2H,d,J=8.6Hz),7.03(1H,dd,J=8.6,2.5Hz),7.11-7.14(2H,m),7.18-7.25(4H,m),7.38(2H,t,J=7.7Hz),7.98(1H,d,J=8.6Hz).Example 51

To a 2.0 mL N, N-dimethylformamide solution of 0.10 g 2- (acetamido) -4-phenoxybenzoic acid, 30 mg 60% sodium hydride was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 0.092 mL of benzyl bromide was added at room temperature, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. To the reaction mixture, 15 mg of 60% sodium hydride was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 0.022 mL of benzyl bromide at room temperature, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. 1.0 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane: ethyl acetate: acetic acid = 40: 10: 1], and colorless oily 2- (N-benzylacetamido) -4-phenoxybenzoic acid 0.10 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.72 (3H, s), 3.93 (1H, d, J = 14.8 Hz), 5.42 (1H, d, J = 14.8 Hz), 6.42 (1H, d, J = 2.5Hz), 6.90 (2H, d, J = 8.6Hz), 7.03 (1H, dd, J = 8.6,2.5Hz), 7.11-7.14 (2H, m), 7.18-7.25 (4H, m), 7.38 (2H, t, J = 7.7Hz), 7.98 (1H, d, J = 8.6Hz).

２−（Ｎ−ベンジルアセトアミド）−４−フェノキシ安息香酸0.10gのヒドラジン一水和物2.0mL懸濁液を3時間加熱還流した。反応混合物を室温まで冷却した後、酢酸5.0mLを加え、酢酸エチルおよび飽和塩化ナトリウム水溶液を加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル：酢酸＝８０：２０：１］で精製し、白色固体の２−（ベンジルアミノ）−４−フェノキシ安息香酸20mgを得た。
¹H-NMR(DMSO-d₆)δ値：4.35(2H,s),6.09(1H,dd,J=8.8,2.4Hz),6.16(1H,d,J=2.4Hz),6.98-7.00(2H,m),7.17-7.27(4H,m),7.30-7.40(4H,m),7.79(1H,d,J=8.8Hz),8.36-8.49(1H,broad),12.32-12.70(1H,broad).Example 52

A suspension of 0.10 g of hydrazine monohydrate in 0.10 g of 2- (N-benzylacetamido) -4-phenoxybenzoic acid was heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, 5.0 mL of acetic acid was added, and ethyl acetate and a saturated aqueous sodium chloride solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate: acetic acid = 80: 20: 1] to obtain 20 mg of 2- (benzylamino) -4-phenoxybenzoic acid as a white solid. .
¹ H-NMR (DMSO-d ₆ ) δ value: 4.35 (2H, s), 6.09 (1H, dd, J = 8.8, 2.4 Hz), 6.16 (1H, d, J = 2.4 Hz), 6.98-7.00 ( 2H, m), 7.17-7.27 (4H, m), 7.30-7.40 (4H, m), 7.79 (1H, d, J = 8.8Hz), 8.36-8.49 (1H, broad), 12.32-12.70 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.20gのＮ，Ｎ−ジメチルホルムアミド2.0mL溶液に、室温で炭酸カリウム0.093gおよびベンジルブロミド0.080mLを加え、同温度で24時間攪拌した。反応混合物に、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝２−（ベンジルアミノ）−４−フェネチルベンゾアート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.56(9H,s),2.76-2.85(4H,m),4.38(2H,d,J=5.4Hz),6.39-6.42(2H,m),7.11-7.34(10H,m),7.78(1H,d,J=8.0Hz),8.10-8.17(1H,broad).Example 53

To a solution of 0.20 g of tert-butyl = 2-amino-4-phenethylbenzoate in 2.0 mL of N, N-dimethylformamide was added 0.093 g of potassium carbonate and 0.080 mL of benzyl bromide at room temperature, and the mixture was stirred at the same temperature for 24 hours. 1.0 mol / L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 5: 1], and tert-butyl = 2- (benzyl) as a colorless oily substance. 0.16 g of amino) -4-phenethylbenzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.56 (9H, s), 2.76-2.85 (4H, m), 4.38 (2H, d, J = 5.4Hz), 6.39-6.42 (2H, m), 7.11- 7.34 (10H, m), 7.78 (1H, d, J = 8.0Hz), 8.10-8.17 (1H, broad).

Examples 54 and 55
In the same manner as in Example 53, the compounds shown in Table 11 were obtained.

tert-butyl = 2- (4-fluorobenzylamino) -4-phenethylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.56 (9H, s), 2.78-2.85 (4H, m), 4.34 (2H, s), 6.34 (1H, d, J = 1.4 Hz), 6.43 (1H, dd, J = 8.1,1.4Hz), 6.98-7.05 (2H, m), 7.11-7.13 (2H, m), 7.16-7.20 (2H, m), 7.24-7.31 (3H, m), 7.79 (1H, d, J = 8.1Hz), 7.98-8.26 (1H, broad).

tert-butyl = 2- (cinnamylamino) -4-phenethylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.57 (9H, s), 2.83 to 2.92 (4H, m), 3.97 (2H, s), 6.29 (1H, dt, J = 16.0, 5.7Hz), 6.44 ( 1H, d, J = 8.2Hz), 6.47 (1H, s), 6.60 (1H, d, J = 16.0Hz), 7.15-7.38 (10H, m), 7.79 (1H, d, J = 8.2Hz), 7.93 (1H, s).

ｔｅｒｔ−ブチル＝２−（ベンジルアミノ）−４−フェネチルベンゾアート0.16gにトリフルオロ酢酸2.0mLを加え、室温で4時間攪拌し、減圧下で溶媒を留去した。トルエンを加え、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の２−（ベンジルアミノ）−４−フェネチル安息香酸0.11gを得た。
¹H-NMR(DMSO-d₆)δ値：2.74-2.81(4H,m),4.41(2H,s),6.44(1H,d,J=8.1Hz),6.57(1H,s),7.14-7.18(3H,m),7.23-7.28(3H,m),7.34-7.36(4H,m),7.69(1H,d,J=8.1Hz).Example 56

To 0.16 g of tert-butyl = 2- (benzylamino) -4-phenethylbenzoate was added 2.0 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. Toluene was added and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to obtain 0.11 g of white solid 2- (benzylamino) -4-phenethylbenzoic acid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.74.2.81 (4H, m), 4.41 (2H, s), 6.44 (1H, d, J = 8.1 Hz), 6.57 (1H, s), 7.14- 7.18 (3H, m), 7.23-7.28 (3H, m), 7.34-7.36 (4H, m), 7.69 (1H, d, J = 8.1Hz).

Examples 57, 58
In the same manner as in Example 56, the compounds shown in Table 12 were obtained.

2- (4-Fluorobenzylamino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.73-2.82 (4H, m), 4.40 (2H, s), 6.44 (1H, dd, J = 8.2, 1.2 Hz), 6.54 (1H, s), 7.13-7.19 (5H, m), 7.22-7.26 (2H, m), 7.36-7.39 (2H, m), 7.68 (1H, d, J = 8.2Hz).

2- (cinnamylamino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80-2.87 (4H, m), 4.00 (2H, d, J = 5.5Hz), 6.38 (1H, dt, J = 15.9, 5.5Hz), 6.46 ( 1H, d, J = 8.0Hz), 6.59-6.63 (2H, m), 7.13-7.27 (6H, m), 7.33 (2H, t, J = 7.6Hz), 7.43 (2H, d, J = 7.6Hz ), 7.69 (1H, d, J = 8.0Hz).

メチル＝２−アミノ−４−フェノキシベンゾアート0.34gのジオキサン5.0mL溶液に、室温で１−フルオロ−４−ヨードベンゼン0.18mL、１，１’−ビス（ジフェニルホスフィノ）フェロセン93mg、１，１’−ビス（ジフェニルホスフィノ）フェロセン＝パラジウム（II）ジクロリド＝塩化メチレンコンプレックス46mgおよびナトリウム＝ｔｅｒｔ−ブトキシド0.15gを加え、窒素雰囲気下、3時間加熱還流した。反応混合物を室温まで冷却した後、10%クエン酸水溶液および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、無色油状物のメチル＝２−（４−フルオロアニリノ）−４−フェノキシベンゾアート0.036gを得た。
¹H-NMR(CDCl₃)δ値：3.88(3H,s),6.26(1H,dd,J=8.9,2.3Hz),6.62(1H,d,J=2.3Hz),6.97-7.04(4H,m),7.12-7.17(3H,m),7.31-7.38(2H,m),7.90(1H,d,J=8.9Hz),9.49(1H,s).Example 59

To a solution of 0.34 g of methyl-2-amino-4-phenoxybenzoate in 5.0 mL of dioxane, 0.18 mL of 1-fluoro-4-iodobenzene, 93 mg of 1,1′-bis (diphenylphosphino) ferrocene at room temperature, 1,1 '-Bis (diphenylphosphino) ferrocene = palladium (II) dichloride = methylene chloride complex (46 mg) and sodium = tert-butoxide (0.15 g) were added, and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 10% aqueous citric acid solution and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 20: 1], and 0.036 g of methyl 2- (4-fluoroanilino) -4-phenoxybenzoate as a colorless oily substance. Got.
¹ H-NMR (CDCl ₃ ) δ value: 3.88 (3H, s), 6.26 (1H, dd, J = 8.9, 2.3 Hz), 6.62 (1H, d, J = 2.3 Hz), 6.97-7.04 (4H, m), 7.12-7.17 (3H, m), 7.31-7.38 (2H, m), 7.90 (1H, d, J = 8.9Hz), 9.49 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−フェノキシベンゾアート36mgのエタノール3.0mL懸濁液に、室温で10%水酸化ナトリウム1.0mLを加え、60℃で1時間30分間攪拌した。反応混合物を室温まで冷却した後、10%水酸化ナトリウム水溶液1.0mLを加え、30分間加熱還流した。反応混合物を室温まで冷却した後、10%クエン酸水溶液および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびヘキサンを加え、不溶物をろ去した。ろ液の溶媒を減圧下で留去し、残留物にヘキサンを加え、固形物をろ取し、白色固体の２−（４−フルオロアニリノ）−４−フェノキシ安息香酸10mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.31(1H,dd,J=8.9,2.3Hz),6.49(1H,d,J=2.3Hz),7.09-7.27(7H,m),7.39-7.44(2H,m),7.89(1H,d,J=8.9Hz),9.66(1H,s),12.79-13.03(1H,broad).Example 60

To a suspension of methyl 2- (4-fluoroanilino) -4-phenoxybenzoate 36 mg in ethanol 3.0 mL was added 10% sodium hydroxide 1.0 mL at room temperature, and the mixture was stirred at 60 ° C. for 1 hour 30 minutes. After the reaction mixture was cooled to room temperature, 10 mL of 10% aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 30 minutes. After the reaction mixture was cooled to room temperature, 10% aqueous citric acid solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the insoluble material was removed by filtration. The solvent of the filtrate was distilled off under reduced pressure, hexane was added to the residue, and the solid was collected by filtration to obtain 10 mg of 2- (4-fluoroanilino) -4-phenoxybenzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.31 (1H, dd, J = 8.9, 2.3 Hz), 6.49 (1H, d, J = 2.3 Hz), 7.09-7.27 (7H, m), 7.39- 7.44 (2H, m), 7.89 (1H, d, J = 8.9Hz), 9.66 (1H, s), 12.79-13.03 (1H, broad).

２−ヨード−４−フェノキシ安息香酸1.5gのＮ，Ｎ−ジメチルホルムアミド15mL溶液に、２，４−ジフルオロアニリン0.67mL、銅粉0.084gおよびＮ−メチルモルホリン1.2mLを加え、100℃で5時間攪拌した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、白色固体の２−（２，４−ジフルオロアニリノ）−４−フェノキシ安息香酸0.60gを得た。
¹H-NMR(DMSO-d₆)δ値：6.29-6.30(1H,m),6.33(1H,dd,J=8.7,2.2Hz),7.04-7.10(3H,m),7.20(1H,t,J=7.4Hz),7.33-7.50(4H,m),7.90(1H,d,J=8.7Hz),9.59(1H,s),12.85-13.19(1H,broad).Example 61

To a solution of 1.5 g of 2-iodo-4-phenoxybenzoic acid in 15 mL of N, N-dimethylformamide is added 0.67 mL of 2,4-difluoroaniline, 0.084 g of copper powder and 1.2 mL of N-methylmorpholine, and at 100 ° C. for 5 hours. Stir. After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 2: 1] to obtain 0.60 g of 2- (2,4-difluoroanilino) -4-phenoxybenzoic acid as a white solid. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.29-6.30 (1H, m), 6.33 (1H, dd, J = 8.7,2.2 Hz), 7.04-7.10 (3H, m), 7.20 (1H, t , J = 7.4Hz), 7.33-7.50 (4H, m), 7.90 (1H, d, J = 8.7Hz), 9.59 (1H, s), 12.85-13.19 (1H, broad).

メチル＝２−（４−フルオロアニリノ）−４−ヨードベンゾアート0.20g、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル10mg、酢酸パラジウム4mgおよび炭酸セシウム0.35gのトルエン2.0mL懸濁液に、アニリン0.074mLを加え、窒素雰囲気下、3時間加熱還流した。反応混合物を室温まで冷却し、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル10mgおよび酢酸パラジウム4mgを加え、窒素雰囲気下、3時間加熱還流した。反応混合物を室温まで冷却し、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、淡黄色固体のメチル＝４−アニリノ−２−（４−フルオロアニリノ）ベンゾアート0.13gを得た。
¹H-NMR(DMSO-d₆)δ値：3.78(3H,s),6.42(1H,dd,J=8.9,2.2Hz),6.63(1H,d,J=2.2Hz),6.95(1H,t,J=7.4Hz),7.10(2H,d,J=7.6Hz),7.19-7.32(6H,m),7.74(1H,d,J=8.9Hz),8.65(1H,s),9.36(1H,s).Example 62

Methyl 2- (4-fluoroanilino) -4-iodobenzoate 0.20 g, rac-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl 10 mg, palladium acetate 4 mg and cesium carbonate 0.35 g To a 2.0 mL suspension of toluene, 0.074 mL of aniline was added and heated to reflux for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (10 mg) and palladium acetate (4 mg) were added, and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1], and methyl = 4-anilino-2-light yellow solid. 0.13 g of (4-fluoroanilino) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.78 (3H, s), 6.42 (1H, dd, J = 8.9, 2.2 Hz), 6.63 (1H, d, J = 2.2 Hz), 6.95 (1H, t, J = 7.4Hz), 7.10 (2H, d, J = 7.6Hz), 7.19-7.32 (6H, m), 7.74 (1H, d, J = 8.9Hz), 8.65 (1H, s), 9.36 ( 1H, s).

メチル＝４−アニリノ−２−（４−フルオロアニリノ）ベンゾアート0.25gのエタノール2.0mL懸濁液に、室温で水酸化ナトリウム0.060gの水1.0mL溶液を加え、2時間加熱還流した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の４−アニリノ−２−（４−フルオロアニリノ）安息香酸0.24gを得た。
¹H-NMR(DMSO-d₆)δ値：6.40(1H,dd,J=8.9,2.2Hz),6.64(1H,d,J=2.2Hz),6.91-6.95(1H,m),7.09-7.12(2H,m),7.17-7.23(2H,m),7.26-7.32(4H,m),7.73(1H,d,J=8.9Hz),8.60(1H,s),9.64(1H,s).Example 63

To a 2.0 mL ethanol suspension of methyl 4-anilino-2- (4-fluoroanilino) benzoate (0.25 g) was added 0.060 g of water (1.0 mL) in water at room temperature, and the mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to obtain 0.24 g of 4-anilino-2- (4-fluoroanilino) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.40 (1H, dd, J = 8.9, 2.2 Hz), 6.64 (1H, d, J = 2.2 Hz), 6.91-6.95 (1H, m), 7.09- 7.12 (2H, m), 7.17-7.23 (2H, m), 7.26-7.32 (4H, m), 7.73 (1H, d, J = 8.9Hz), 8.60 (1H, s), 9.64 (1H, s) .

メチル＝２−（４−フルオロアニリノ）−４−ヨードベンゾアート0.30gのトルエン3.0mL溶液に、室温でベンジルアミン0.13mL、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル0.050g、トリス（ジベンジリデンアセトン）ジパラジウム（０）0.022gおよびナトリウム＝ｔｅｒｔ−ブトキシド0.093gを加え、窒素雰囲気下、80℃で1時間攪拌した。反応混合物を室温まで冷却した後、酢酸1.0mLを加え、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、褐色油状物のメチル＝４−（ベンジルアミノ）−２−（４−フルオロアニリノ）ベンゾアート0.24gを得た。
¹H-NMR(CDCl₃)δ値：3.82(3H,s),4.27(2H,s),6.03(1H,dd,J=8.9,2.1Hz),6.09(1H,d,J=2.1Hz),6.90-6.95(2H,m),7.01-7.04(2H,m),7.25-7.35(5H,m),7.77(1H,d,J=8.9Hz),9.47(1H,s).Example 64

Methyl 2- (4-fluoroanilino) -4-iodobenzoate 0.30 g in a toluene 3.0 mL solution at room temperature with benzylamine 0.13 mL, rac-2,2′-bis (diphenylphosphino) -1,1 0.050 g of '-binaphthyl, 0.022 g of tris (dibenzylideneacetone) dipalladium (0) and 0.093 g of sodium = tert-butoxide were added, and the mixture was stirred at 80 ° C. for 1 hour in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 1.0 mL of acetic acid was added, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 5: 1] to give methyl 4- (benzylamino) -2- (4-fluoroanilino) benzoate as a brown oil. Obtained 0.24 g of art.
¹ H-NMR (CDCl ₃ ) δ value: 3.82 (3H, s), 4.27 (2H, s), 6.03 (1H, dd, J = 8.9, 2.1 Hz), 6.09 (1H, d, J = 2.1 Hz) 6.90-6.95 (2H, m), 7.01-7.04 (2H, m), 7.25-7.35 (5H, m), 7.77 (1H, d, J = 8.9Hz), 9.47 (1H, s).

Examples 65, 66
In the same manner as in Example 64, the compounds shown in Table 13 were obtained.

Methyl 2- (4-fluoroanilino) -4- (phenethylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 2.84 (2H, t, 7.1 Hz), 3.32 (2H, t, 7.1 Hz), 3.83 (3H, s), 3.98-4.08 (1H, broad), 5.97 (1H , dd, J = 8.8,2.2Hz), 6.13 (1H, d, J = 2.2Hz), 7.02-7.07 (2H, m), 7.13-7.31 (7H, m), 7.77 (1H, d, J = 8.8 Hz), 9.48 (1H, s).

Methyl = 2- (4-fluoroanilino) -4-((3-phenylpropyl) amino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.85-1.93 (2H, m), 2.67 (2H, t, 7.6Hz), 3.07 (2H, t, 6.9Hz), 3.83 (3H, s), 3.91-3.98 (1H, broad), 5.93 (1H, dd, J = 8.8,2.2Hz), 6.07 (1H, d, J = 2.2Hz), 7.00-7.05 (2H, m), 7.14-7.30 (7H, m), 7.76 (1H, d, J = 8.8Hz), 9.47 (1H, s).

メチル＝４−（ベンジルアミノ）−２−（４−フルオロアニリノ）ベンゾアート0.24gのエタノール3.0mL懸濁液に、室温で10％水酸化ナトリウム水溶液0.82mLを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、10％水酸化ナトリウム水溶液0.82mLを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、酢酸2.0mL、飽和塩化ナトリウム水溶液および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の４−（ベンジルアミノ）−２−（４−フルオロアニリノ）安息香酸0.17gを得た。
¹H-NMR(DMSO-d₆)δ値：4.22(2H,d,J=5.6Hz),6.07-6.09(2H,m),6.99-7.08(5H,m),7.24-7.27(3H,m),7.32-7.35(2H,m),7.60(1H,d,J=8.8Hz),9.55-9.90(1H,broad).Example 67

To a suspension of ethanol in 0.24 g of methyl 4- (benzylamino) -2- (4-fluoroanilino) benzoate in 3.0 mL of ethanol was added 0.82 mL of 10% aqueous sodium hydroxide at room temperature, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, 0.82 mL of 10% aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, 2.0 mL of acetic acid, saturated aqueous sodium chloride solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to obtain 0.17 g of 4- (benzylamino) -2- (4-fluoroanilino) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 4.22 (2H, d, J = 5.6 Hz), 6.07-6.09 (2H, m), 6.99-7.08 (5H, m), 7.24-7.27 (3H, m ), 7.32-7.35 (2H, m), 7.60 (1H, d, J = 8.8Hz), 9.55-9.90 (1H, broad).

Examples 68 and 69
In the same manner as in Example 67, the compounds shown in Table 14 were obtained.

2- (4-Fluoroanilino) -4- (phenethylamino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.75 (2H, t, 7.6 Hz), 3.15-3.20 (2H, m), 6.04 (1H, dd, J = 8.9, 2.1 Hz), 6.16 (1H, d, J = 2.1Hz), 6.50 (1H, t, 5.5Hz), 7.16-7.29 (9H, m), 7.62 (1H, d, J = 8.9Hz), 9.68 (1H, s), 12.02 (1H, s).

2- (4-Fluoroanilino) -4-((3-phenylpropyl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.74-1.81 (2H, m), 2.62 (2H, t, 7.7 Hz), 2.93-2.98 (2H, m), 6.00 (1H, dd, J = 9.0 2.1Hz), 6.14 (1H, d, J = 2.1Hz), 6.41 (1H, t, 5.3Hz), 7.15-7.28 (9H, m), 7.61 (1H, d, J = 9.0Hz), 9.67 ( 1H, s), 12.00 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−ヨードベンゾアート0.20gの２−メチル−２−プロパノール4.0mL溶液に、ベンゼンチオール0.067mL、テトラキス（トリフェニルホスフィン）パラジウム（０）0.03gおよびナトリウム＝ｔｅｒｔ−ブトキシド0.10gを加え、窒素雰囲気下、30分間加熱還流した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学社製、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、無色油状物のメチル＝２−（４−フルオロアニリノ）−４−（フェニルチオ）ベンゾアート30mgを得た。
¹H-NMR(CDCl₃)δ値：3.87(3H,s),6.49(1H,dd,J=8.5,1.8Hz),6.71(1H,d,J=1.8Hz),6.91-6.96(2H,m),7.00-7.04(2H,m),7.34-7.37(3H,m),7.44-7.47(2H,m),7.80(1H,d,J=8.5Hz),9.37(1H,s).Example 70

To a solution of 0.20 g of methyl 2- (4-fluoroanilino) -4-iodobenzoate in 4.0 mL of 2-methyl-2-propanol, 0.067 mL of benzenethiol, 0.03 g of tetrakis (triphenylphosphine) palladium (0) and Sodium = tert-butoxide (0.10 g) was added, and the mixture was heated to reflux for 30 minutes under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [manufactured by Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 20: 1] to give a colorless oily methyl 2- (4-fluoro 30 mg of anilino) -4- (phenylthio) benzoate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.87 (3H, s), 6.49 (1H, dd, J = 8.5, 1.8 Hz), 6.71 (1H, d, J = 1.8 Hz), 6.91-6.96 (2H, m), 7.00-7.04 (2H, m), 7.34-7.37 (3H, m), 7.44-7.47 (2H, m), 7.80 (1H, d, J = 8.5Hz), 9.37 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−（フェニルチオ）ベンゾアート0.21gの２−プロパノール2.0mL懸濁液に、室温で10％水酸化ナトリウム水溶液1.0mLを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色固体の２−（４−フルオロアニリノ）−４−（フェニルチオ）安息香酸0.16gを得た。
¹H-NMR(DMSO-d₆)δ値：6.54-6.59(2H,m),7.06-7.13(4H,m),7.42-7.51(5H,m),7.80(1H,d,J=8.3Hz),9.55(1H,s).Example 71

To a suspension of 0.21 g of methyl 2- (4-fluoroanilino) -4- (phenylthio) benzoate in 2.0 mL of 2-propanol was added 1.0 mL of 10% aqueous sodium hydroxide at room temperature, and the mixture was heated to reflux for 2 hours. . After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.16 g of 2- (4-fluoroanilino) -4- (phenylthio) benzoic acid as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.54-6.59 (2H, m), 7.06-7.13 (4H, m), 7.42-7.51 (5H, m), 7.80 (1H, d, J = 8.3Hz ), 9.55 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−ヨードベンゾアート0.40g、１，１’−ビス（ジフェニルホスフィノ）フェロセン0.072gおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）0.050gのトルエン4.0mL懸濁液に、トリエチルアミン0.30mLおよびフェニルメタンチオール0.15mLを加え、アルゴン雰囲気下、80℃で2時間攪拌した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、白色固体のメチル＝４−（ベンジルチオ）−２−（４−フルオロアニリノ）ベンゾアート0.36gを得た。
¹H-NMR(CDCl₃)δ値：3.87(3H,s),4.06(2H,s),6.61(1H,dd,J=8.5,1.5Hz),6.79(1H,d,J=1.5Hz),6.98-7.08(4H,m),7.23-7.28(5H,m),7.81(1H,d,J=8.5Hz),9.36(1H,s).Example 72

Methyl 2- (4-fluoroanilino) -4-iodobenzoate 0.40 g, 1,1′-bis (diphenylphosphino) ferrocene 0.072 g and tris (dibenzylideneacetone) dipalladium (0) 0.050 g of toluene To the 4.0 mL suspension were added triethylamine 0.30 mL and phenylmethanethiol 0.15 mL, and the mixture was stirred at 80 ° C. for 2 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: hexane: ethyl acetate = 10: 1], and white solid methyl = 4- (benzylthio) -2 0.36 g of-(4-fluoroanilino) benzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.87 (3H, s), 4.06 (2H, s), 6.61 (1H, dd, J = 8.5, 1.5 Hz), 6.79 (1H, d, J = 1.5 Hz) 6.98-7.08 (4H, m), 7.23-7.28 (5H, m), 7.81 (1H, d, J = 8.5Hz), 9.36 (1H, s).

メチル＝４−（ベンジルチオ）−２−（４−フルオロアニリノ）ベンゾアート0.36gの２−プロパノール4.0mL懸濁液に、室温で10％水酸化ナトリウム水溶液1.0mLを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の４−（ベンジルチオ）−２−（４−フルオロアニリノ）安息香酸0.30gを得た。
¹H-NMR(DMSO-d₆)δ値：4.20(2H,s),6.69(1H,dd,J=8.5,1.7Hz),6.78(1H,dd,J=3.9,1.7Hz),7.18-7.29(9H,m),7.76(1H,d,J=8.5Hz),9.56(1H,s).Example 73

To a suspension of 0.36 g of methyl 4- (benzylthio) -2- (4-fluoroanilino) benzoate in 4.0 mL of 2-propanol was added 1.0 mL of 10% aqueous sodium hydroxide at room temperature, and the mixture was heated to reflux for 2 hours. . After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to obtain 0.30 g of 4- (benzylthio) -2- (4-fluoroanilino) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 4.20 (2H, s), 6.69 (1H, dd, J = 8.5, 1.7 Hz), 6.78 (1H, dd, J = 3.9, 1.7 Hz), 7.18- 7.29 (9H, m), 7.76 (1H, d, J = 8.5Hz), 9.56 (1H, s).

メチル＝２−アミノ−４−（（フェニルチオ）メチル）ベンゾアート塩酸塩0.96g、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル19mg、酢酸パラジウム7mgおよび炭酸セシウム3.0gのトルエン9.5mL懸濁液に、１−フルオロ−４−ヨードベンゼン1.1mLを加え、窒素雰囲気下、3時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム7.0mgを加え、14時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、淡黄色油状物のメチル＝２−（４−フルオロアニリノ）−４−（（フェニルチオ）メチル）ベンゾアート0.48gを得た。
¹H-NMR(CDCl₃)δ値：3.88(3H,s),3.94(2H,s),6.67(1H,dd,J=8.3,1.5Hz),6.84(1H,d,J=1.5Hz),6.95-7.02(4H,m),7.20-7.28(5H,m),7.88(1H,d,J=8.3Hz),9.33(1H,s).Example 74

0.96 g of methyl = 2-amino-4-((phenylthio) methyl) benzoate hydrochloride, 19 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 7 mg of palladium acetate and cesium carbonate 3.0 To a 9.5 mL suspension of g in toluene was added 1.1 mL of 1-fluoro-4-iodobenzene, and the mixture was heated to reflux for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 7.0 mg of palladium acetate was added, and the mixture was heated to reflux for 14 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 20: 1], and methyl 2- (4- 0.48 g of fluoroanilino) -4-((phenylthio) methyl) benzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.88 (3H, s), 3.94 (2H, s), 6.67 (1H, dd, J = 8.3, 1.5 Hz), 6.84 (1H, d, J = 1.5 Hz) 6.95-7.02 (4H, m), 7.20-7.28 (5H, m), 7.88 (1H, d, J = 8.3Hz), 9.33 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−（（フェニルチオ）メチル）ベンゾアート0.48gのメタノール2.4mLおよびテトラヒドロフラン2.4mL混液に、2.0mol/L水酸化ナトリウム水溶液2.0mLを加え、室温で17時間攪拌した。減圧下で溶媒を留去し、酢酸エチルおよび水を加え、1.0mol/L塩酸でpH4.0に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、ヘキサンおよびジイソプロピルエーテルを加え、固形物をろ取し、淡黄色固体の２−（４−フルオロアニリノ）−４−（（フェニルチオ）メチル）安息香酸0.40gを得た。
¹H-NMR(DMSO-d₆)δ値：4.14(2H,s),6.76(1H,d,J=8.2Hz),6.97-6.98(1H,m),7.06-7.10(2H,m),7.12-7.18(2H,m),7.20-7.25(1H,m),7.30-7.31(4H,m),7.81(1H,d,J=8.2Hz),9.51(1H,s),12.94-13.03(1H,broad).Example 75

To a mixed solution of methyl 8- (4-fluoroanilino) -4-((phenylthio) methyl) benzoate (0.48 g) in methanol (2.4 mL) and tetrahydrofuran (2.4 mL) was added 2.0 mol / L sodium hydroxide aqueous solution (2.0 mL), and at room temperature. Stir for 17 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 4.0 with 1.0 mol / L hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the solid was collected by filtration to obtain 0.40 g of 2- (4-fluoroanilino) -4-((phenylthio) methyl) benzoic acid as a pale yellow solid. .
¹ H-NMR (DMSO-d ₆ ) δ value: 4.14 (2H, s), 6.76 (1H, d, J = 8.2 Hz), 6.97-6.98 (1H, m), 7.06-7.10 (2H, m), 7.12-7.18 (2H, m), 7.20-7.25 (1H, m), 7.30-7.31 (4H, m), 7.81 (1H, d, J = 8.2Hz), 9.51 (1H, s), 12.94-13.03 ( 1H, broad).

メチル＝２−アミノ−４−（フェノキシメチル）ベンゾアート塩酸塩0.40g、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル8mg、酢酸パラジウム3mgおよび炭酸セシウム0.89gのトルエン4.0mL懸濁液に、１−フルオロ−４−ヨードベンゼン0.47mLを加え、窒素雰囲気下、16時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、淡黄色油状物のメチル＝２−（４−フルオロアニリノ）−４−（フェノキシメチル）ベンゾアート0.22gを得た。
¹H-NMR(CDCl₃)δ値：3.90(3H,s),4.98(2H,s),6.76(1H,dd,J=8.3,1.7Hz),6.88-7.03(5H,m),7.09-7.14(3H,m),7.25-7.30(6H,m),7.96(1H,d,J=8.3Hz),9.40(1H,s).Example 76

0.40 g of methyl-2-amino-4- (phenoxymethyl) benzoate hydrochloride, 8 mg of rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, 3 mg of palladium acetate and 0.89 g of cesium carbonate To a toluene 4.0 mL suspension, 0.47 mL of 1-fluoro-4-iodobenzene was added and heated to reflux for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 20: 1] and methyl 2- (4-fluoroanilino) -4- (phenoxymethyl) as a pale yellow oily substance. 0.22 g of benzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 3.90 (3H, s), 4.98 (2H, s), 6.76 (1H, dd, J = 8.3, 1.7 Hz), 6.88-7.03 (5H, m), 7.09- 7.14 (3H, m), 7.25-7.30 (6H, m), 7.96 (1H, d, J = 8.3Hz), 9.40 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−（フェノキシメチル）ベンゾアート0.22gのメタノール2.0mLおよびテトラヒドロフラン2.0mL混液に、2.0mol/L水酸化ナトリウム水溶液0.92mLを加え、室温で24時間攪拌した。減圧下で溶媒を留去し、水を加え、1.0mol/L塩酸でpH4.0に調整した。固形物をろ取し、白色固体の２−（４−フルオロアニリノ）−４−（フェノキシメチル）安息香酸0.14gを得た。
¹H-NMR(DMSO-d₆)δ値：5.07(2H,s),6.81(1H,dd,J=8.2,1.3Hz),6.92-6.96(3H,m),7.12-7.22(5H,m),7.26-7.31(2H,m),7.90(1H,d,J=8.2Hz).Example 77

To a mixed solution of methyl 2- (4-fluoroanilino) -4- (phenoxymethyl) benzoate 0.22 g of methanol 2.0 mL and tetrahydrofuran 2.0 mL, 2.0 mol / L aqueous sodium hydroxide solution 0.92 mL was added, and the mixture was stirred at room temperature for 24 hours. Stir. The solvent was distilled off under reduced pressure, water was added, and the pH was adjusted to 4.0 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration to obtain 0.14 g of 2- (4-fluoroanilino) -4- (phenoxymethyl) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 5.07 (2H, s), 6.81 (1H, dd, J = 8.2, 1.3 Hz), 6.92-6.96 (3H, m), 7.12-7.22 (5H, m ), 7.26-7.31 (2H, m), 7.90 (1H, d, J = 8.2Hz).

メチル＝２−（４−フルオロアニリノ）−４−ヨードベンゾアート0.30g、アリルベンゼン0.16mLおよびトリエチルアミン0.11mLのトルエン3.0mL溶液に、酢酸パラジウム9mgを加え、窒素雰囲気下、2時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム18mgを加え、窒素雰囲気下、2時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム18mgを加え、窒素雰囲気下、1時間加熱還流した。反応混合物を室温まで冷却した後、酢酸パラジウム18mgを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、メチル＝２−（４−フルオロアニリノ）−４−（３−フェニル−１−プロペニル）ベンゾアートを得た。
得られたメチル＝２−（４−フルオロアニリノ）−４−（３−フェニル−１−プロペニル）ベンゾアートのメタノール8mLおよび酢酸エチル2mL混液に、5％パラジウム−炭素0.060gを加え、水素雰囲気下、室温で1時間攪拌した。反応混合物の不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、無色油状物のメチル＝２−（４−フルオロアニリノ）−４−（３−フェニルプロピル）ベンゾアート0.10gを得た。
¹H-NMR(CDCl₃)δ値：1.85-1.93(2H,m),2.53(2H,t,J=7.6Hz),2.61(2H,t,J=7.6Hz),3.88(3H,s),6.56(1H,d,J=8.3Hz),6.86(1H,s),7.03-7.07(2H,m),7.13-7.28(7H,m),7.87(1H,d,J=8.3Hz),9.34(1H,s).Example 78

To a solution of methyl 2- (4-fluoroanilino) -4-iodobenzoate 0.30 g, allylbenzene 0.16 mL and triethylamine 0.11 mL in toluene 3.0 mL was added 9 mg of palladium acetate, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. . The reaction mixture was cooled to room temperature, 18 mg of palladium acetate was added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 18 mg of palladium acetate was added, and the mixture was heated to reflux for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 18 mg of palladium acetate was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 20: 1] and methyl = 2- (4-fluoroanilino) -4- (3-phenyl-1-propenyl). I got benzoart.
To the resulting mixture of methyl 2- (4-fluoroanilino) -4- (3-phenyl-1-propenyl) benzoate in 8 mL of methanol and 2 mL of ethyl acetate was added 0.060 g of 5% palladium-carbon, and a hydrogen atmosphere. The mixture was stirred at room temperature for 1 hour. Insoluble matter in the reaction mixture was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and methyl oil as a colorless oil = 2- (4-fluoroanilino) 0.10 g of -4- (3-phenylpropyl) benzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.85-1.93 (2H, m), 2.53 (2H, t, J = 7.6Hz), 2.61 (2H, t, J = 7.6Hz), 3.88 (3H, s) , 6.56 (1H, d, J = 8.3Hz), 6.86 (1H, s), 7.03-7.07 (2H, m), 7.13-7.28 (7H, m), 7.87 (1H, d, J = 8.3Hz), 9.34 (1H, s).

Examples 79 and 80
In the same manner as in Example 78, the compounds shown in Table 15 were obtained.

Methyl = 2 (4-fluoroanilino) -4- (4-phenylbutyl) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.58-1.64 (4H, m), 2.51 (2H, t, J = 6.9 Hz), 2.60 (2H, t, J = 7.2 Hz), 3.88 (3H, s) , 6.54 (1H, dd, J = 8.2,1.5Hz), 6.84 (1H, d, 1.5Hz), 7.00-7.05 (2H, m), 7.12-7.28 (7H, m), 7.85 (1H, d, J = 8.2Hz), 9.33 (1H, s).

Methyl = 2 (4-fluoroanilino) -4- (5-phenylpentyl) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.30-1.38 (2H, m), 1.51-1.65 (4H, m), 2.48 (2H, t, J = 7.8Hz), 2.58 (2H, t, J = 7.7 Hz), 3.88 (3H, s), 6.54 (1H, dd, J = 8.3, 1.6Hz), 6.85 (1H, d, J = 1.6Hz), 7.01-7.07 (2H, m), 7.13-7.28 (7H , m), 7.86 (1H, d, J = 8.3Hz), 9.34 (1H, s).

メチル＝２−（４−フルオロアニリノ）−４−（３−フェニルプロピル）ベンゾアート0.10gのエタノール2.0mL懸濁液に、室温で10％水酸化ナトリウム水溶液0.2mLを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、白色固体の２−（４−フルオロアニリノ）−４−（３−フェニルプロピル）安息香酸70mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.78-1.86(2H,m),2.48-2.58(4H,m),6.62(1H,d,J=8.1Hz),6.87(1H,s),7.15-7.30(9H,m),7.81(1H,d,J=8.1Hz),9.53(1H,s),12.74-13.01(1H,broad).Example 81

Methyl 2- (4-fluoroanilino) -4- (3-phenylpropyl) benzoate (0.10 g) in ethanol (2.0 mL) suspension at room temperature was added 10% aqueous sodium hydroxide solution (0.2 mL) and heated under reflux for 2 hours. did. After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid was collected by filtration to obtain 70 mg of 2- (4-fluoroanilino) -4- (3-phenylpropyl) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.78-1.86 (2H, m), 2.48-2.58 (4H, m), 6.62 (1H, d, J = 8.1 Hz), 6.87 (1H, s), 7.15-7.30 (9H, m), 7.81 (1H, d, J = 8.1Hz), 9.53 (1H, s), 12.74-13.01 (1H, broad).

Examples 82 and 83
In the same manner as in Example 81, the compounds shown in Table 16 were obtained.

2- (4-Fluoroanilino) -4- (4-phenylbutyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.52-1.56 (4H, m), 2.49-2.56 (4H, m), 6.60 (1H, d, J = 8.3 Hz), 6.87 (1H, s), 7.13-7.20 (5H, m), 7.23-7.28 (4H, m), 7.79 (1H, d, J = 8.3Hz), 9.51 (1H, s), 12.75-13.02 (1H, broad).

2- (4-Fluoroanilino) -4- (5-phenylpentyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.23-1.31 (2H, m), 1.49-1.59 (4H, m), 2.45-2.55 (4H, m), 6.60 (1H, d, J = 8.3Hz ), 6.88 (1H, d, J = 2.7Hz), 7.10-7.28 (9H, m), 7.79 (1H, d, J = 8.3Hz), 9.52 (1H, s), 12.77-12.98 (1H, broad) .

２−ヨード−４−フェネチル安息香酸0.20gのジメチルスルホキシド2.0mL溶液に、フェネチルアミン0.11mL、ヨウ化銅（I）0.010g、プロリン0.013gおよび炭酸カリウム0.16gを加え、60℃で4時間攪拌した。反応混合物を室温まで冷却した後、1.0mol/L塩酸および酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル：酢酸＝９０：１０：１］で精製し、白色固体の４−フェネチル−２−（フェネチルアミノ）安息香酸0.12gを得た。
¹H-NMR(DMSO-d₆)δ値：2.80-2.90(6H,m),3.37(2H,t,J=7.1Hz),6.45(1H,dd,J=8.1,1.3Hz),6.57(1H,s),7.14-7.33(10H,m),7.67(1H,d,J=8.1Hz).Example 84

To a 2.0 mL solution of 0.20 g 2-iodo-4-phenethylbenzoic acid in dimethyl sulfoxide was added 0.11 mL phenethylamine, 0.010 g copper (I) iodide, 0.013 g proline and 0.16 g potassium carbonate, and the mixture was stirred at 60 ° C. for 4 hours. . After the reaction mixture was cooled to room temperature, 1.0 mol / L hydrochloric acid and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical, PSQ100B (spherical), eluent; hexane: ethyl acetate: acetic acid = 90: 10: 1], and white solid 4-phenethyl-2- ( 0.12 g of phenethylamino) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80-2.90 (6H, m), 3.37 (2H, t, J = 7.1 Hz), 6.45 (1H, dd, J = 8.1, 1.3 Hz), 6.57 ( 1H, s), 7.14-7.33 (10H, m), 7.67 (1H, d, J = 8.1Hz).

実施例８４と同様にして以下の化合物を得た。
２−（シクロヘキシルアミノ）−４−フェネチル安息香酸
¹H-NMR(DMSO-d₆)δ値：1.10-1.44(5H,m),1.52-1.72(3H,m),1.79-1.90(2H,m),2.81-2.88(4H,m),3.26-3.36(1H,m),6.41(1H,d,J=8.2Hz),6.49(1H,s),7.15-7.28(5H,m),7.67(1H,d,J=8.2Hz),7.70-7.90(1H,broad),12.21-12.48(1H,broad).Example 85

The following compounds were obtained in the same manner as in Example 84.
2- (Cyclohexylamino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.10-1.44 (5H, m), 1.52-1.72 (3H, m), 1.79-1.90 (2H, m), 2.81-2.88 (4H, m), 3.26 -3.36 (1H, m), 6.41 (1H, d, J = 8.2Hz), 6.49 (1H, s), 7.15-7.28 (5H, m), 7.67 (1H, d, J = 8.2Hz), 7.70- 7.90 (1H, broad), 12.21-12.48 (1H, broad).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.20gのトルエン2.0mL、エタノール0.6mLおよび水0.2mL混液に、（Ｅ）−２−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）スチレン0.21g、炭酸水素ナトリウム0.18gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）40mgを加え、窒素雰囲気下、2時間加熱還流した。反応混合物を室温まで冷却した後、テトラキス（トリフェニルホスフィン）パラジウム（０）40mgを加え、窒素雰囲気下、6時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、1.0mol/L塩酸、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、メチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−フェニルビニル）ベンゾアートを得た。
得られたメチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−フェニルビニル）ベンゾアートのメタノール2mLおよびテトラヒドロフラン2mL混液に、室温で2.0mol/L水酸化ナトリウム水溶液2.5mLを加え、室温で4時間攪拌した。減圧下で溶媒を留去し、水を加え、1.0mol/L塩酸でpH4.0に調整した。固形物をろ取し、シリカゲルカラムクロマトグラフィー［溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、２−（４−フルオロアニリノ）−４−（（Ｅ）−２−フェニルビニル）安息香酸58mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.11(1H,dd,J=8.4,1.3Hz),7.18-7.38(10H,m),7.61-7.63(2H,m),7.89(1H,d,J=8.4Hz),9.60(1H,s),12.97-13.05(1H,broad).Example 86

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 0.20 g of toluene 2.0 mL, ethanol 0.6 mL and water 0.2 mL were mixed with (E) -2- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) styrene (0.21 g), sodium hydrogencarbonate (0.18 g) and tetrakis (triphenylphosphine) palladium (0) (40 mg) were added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and the mixture was heated to reflux for 6 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 20: 1] and methyl = 2- (4-fluoroanilino) -4-((E) -2-phenylvinyl. I got benzoart.
The resulting methyl 2- (4-fluoroanilino) -4-((E) -2-phenylvinyl) benzoate in a mixture of 2 mL of methanol and 2 mL of tetrahydrofuran was mixed with 2.5 mL of a 2.0 mol / L aqueous sodium hydroxide solution at room temperature. And stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, water was added, and the pH was adjusted to 4.0 with 1.0 mol / L hydrochloric acid. The solid was collected by filtration and purified by silica gel column chromatography [eluent: hexane: ethyl acetate = 2: 1] to give 2- (4-fluoroanilino) -4-((E) -2-phenylvinyl). Benzoic acid 58 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.11 (1H, dd, J = 8.4, 1.3 Hz), 7.18-7.38 (10H, m), 7.61-7.63 (2H, m), 7.89 (1H, d , J = 8.4Hz), 9.60 (1H, s), 12.97-13.05 (1H, broad).

ｔｅｒｔ−ブチル＝４−アミノ−２−（４−フルオロアニリノ）ベンゾアート40mgの塩化メチレン3.0mL溶液に、室温でトリエチルアミン0.064mL、ベンゾチオフェン−３−カルボニルクロリド55mgおよび塩化メチレン1.5mLを加え、同温度で2時間攪拌した。反応混合物に、アミノメチレイティッドポリスチレン250mgを加え、室温で4時間攪拌した。反応混合物に、飽和炭酸水素ナトリウム水溶液を加え、不溶物をろ去した。有機層を分取し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝4：１］で精製し、ｔｅｒｔ−ブチル＝４−（ベンゾチオフェン−３−カルボキサミド）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（ベンゾチオフェン−３−カルボキサミド）−２−（４−フルオロアニリノ）ベンゾアートに、トリフルオロ酢酸5mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の４−（ベンゾチオフェン−３−カルボキサミド）−２−（４−フルオロアニリノ）安息香酸24mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.21-7.36(5H,m),7.44-7.48(2H,m),7.65(1H,d,J=2.0Hz),7.89(1H,d,J=8.8Hz),8.07(1H,dd,J=6.7,1.8Hz),8.34-8.36(1H,m),8.56(1H,s),9.66(1H,s),10.42(1H,s),12.80-12.90(1H,broad).Example 87

To a solution of 40 mg of tert-butyl 4-amino-2- (4-fluoroanilino) benzoate in 3.0 mL of methylene chloride was added 0.064 mL of triethylamine, 55 mg of benzothiophene-3-carbonyl chloride and 1.5 mL of methylene chloride at room temperature, The mixture was stirred at the same temperature for 2 hours. To the reaction mixture, 250 mg of aminomethylated polystyrene was added and stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the insoluble material was removed by filtration. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 4- (benzothiophene-3-carboxamide)- 2- (4-Fluoroanilino) benzoate was obtained.
To the obtained tert-butyl 4- (benzothiophene-3-carboxamido) -2- (4-fluoroanilino) benzoate, 5 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and white solid 4- (benzothiophene-3-carboxamide) -2- (4-fluoroanilino) 24 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.21-7.36 (5H, m), 7.44-7.48 (2H, m), 7.65 (1H, d, J = 2.0Hz), 7.89 (1H, d, J = 8.8Hz), 8.07 (1H, dd, J = 6.7,1.8Hz), 8.34-8.36 (1H, m), 8.56 (1H, s), 9.66 (1H, s), 10.42 (1H, s), 12.80 -12.90 (1H, broad).

Examples 88-91
In the same manner as in Example 87, the compounds shown in Table 17 were obtained.

4- (2,3-Dihydrobenzo [1,4] dioxin-6-carboxamide) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 4.28-4.32 (4H, m), 6.97 (1H, d, J = 8.3Hz), 7.20-7.33 (5H, m), 7.44-7.48 (2H, m ), 7.69 (1H, d, J = 2.0Hz), 7.85 (1H, d, J = 8.8Hz), 9.65 (1H, s), 10.12 (1H, s), 12.78-12.85 (1H, broad).

4- (2,2-diphenylacetamido) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 5.18 (1H, s), 7.08 (1H, dd, J = 8.8, 2.0 Hz), 7.20-7.35 (14H, m), 7.43 (1H, d, J = 2.0Hz), 7.82 (1H, d, J = 8.8Hz), 9.61 (1H, s), 10.48 (1H, s), 12.79-12.85 (1H, broad).

4- (Cinnamamide) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.79 (1H, d, J = 15.6Hz), 7.07 (1H, dd, J = 8.8, 2.0Hz), 7.22-7.26 (2H, m), 7.30- 7.34 (2H, m), 7.39-7.47 (3H, m), 7.56-7.63 (4H, m), 7.86 (1H, d, J = 8.8Hz), 9.64 (1H, s), 10.30 (1H, s) , 12.76-12.84 (1H, broad).

4- (Benzenesulfonamido) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.48 (1H, dd, J = 8.6, 2.0 Hz), 6.76 (1H, d, J = 2.0 Hz), 7.07-7.11 (2H, m), 7.21- 7.25 (2H, m), 7.57-7.61 (2H, m), 7.64-7.68 (1H, m), 7.71-7.73 (3H, m), 10.57-10.66 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、２，４−ジフルオロ−１−ヨードベンゼン0.10mL、炭酸セシウム0.22g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、トリス（ジベンジリデンアセトン）ジパラジウム（０）3mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル：酢酸＝２０：１：１］で精製し、ｔｅｒｔ−ブチル＝２−（２，４−ジフルオロアニリノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（２，４−ジフルオロアニリノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、白色固体の２−（２，４−ジフルオロアニリノ）−４−フェネチル安息香酸59mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.82(4H,s),6.65(1H,s),6.70(1H,dd,J=8.1,1.5Hz),7.05(1H,tdd,J=8.6,2.8,1.3Hz),7.14-7.21(3H,m),7.23-7.30(3H,m),7.37(1H,ddd,J=11.1,8.9,2.8Hz),7.81(1H,d,J=8.1Hz),9.46(1H,s),12.85-13.20(1H,broad).Example 92

To a 3.0 mL toluene solution of 0.10 g tert-butyl = 2-amino-4-phenethylbenzoate, 0.10 mL 2,4-difluoro-1-iodobenzene, 0.22 g cesium carbonate, tris (dibenzylideneacetone) dipalladium (0 ) 3 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 8 mg were added and stirred at 110 ° C. for 24 hours. After cooling the reaction mixture to room temperature, 3 mg of tris (dibenzylideneacetone) dipalladium (0) and 8 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added, and the mixture was stirred at 110 ° C. for 24 hours. did. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate: acetic acid = 20: 1: 1], and tert-butyl = 2 (2,4- Difluoroanilino) -4-phenethylbenzoate was obtained.
To the obtained tert-butyl = 2- (2,4-difluoroanilino) -4-phenethylbenzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, methanol was added to the obtained residue, and the solid was collected by filtration to obtain 59 mg of 2- (2,4-difluoroanilino) -4-phenethylbenzoic acid as a white solid. .
¹ H-NMR (DMSO-d ₆ ) δ value: 2.82 (4H, s), 6.65 (1H, s), 6.70 (1H, dd, J = 8.1, 1.5 Hz), 7.05 (1H, tdd, J = 8.6 , 2.8,1.3Hz), 7.14-7.21 (3H, m), 7.23-7.30 (3H, m), 7.37 (1H, ddd, J = 11.1,8.9,2.8Hz), 7.81 (1H, d, J = 8.1 Hz), 9.46 (1H, s), 12.85-13.20 (1H, broad).

Examples 93-100
In the same manner as in Example 92, the compounds shown in Table 18 were obtained.

2-((2,3-Dihydrobenzo [1,4] dioxin-6-yl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ values: 2.74-2.86 (4H, m), 4.21-4.28 (4H, m), 6.54 (1H, dd, J = 8.7,2.5Hz), 6.60 (1H, dd , J = 8.3,1.4Hz), 6.67 (1H, d, J = 2.5Hz), 6.78-6.83 (2H, m), 7.14-7.20 (3H, m), 7.22-7.29 (2H, m), 7.76 ( 1H, d, J = 8.3Hz), 9.39 (1H, s), 12.81 (1H, s).

2- (3-Fluoro-4-methylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.19 (3H, d, J = 1.0 Hz), 2.84 (4H, s), 6.71 (1H, dd, J = 8.2, 1.2 Hz), 6.79 (1H, dd, J = 8.2,2.1Hz), 6.91 (1H, dd, J = 11.6,2.1Hz), 6.96 (1H, d, J = 1.2Hz), 7.14-7.22 (4H, m), 7.23-7.30 (2H , m), 7.81 (1H, d, J = 8.3Hz), 9.56 (1H, s), 12.95 (1H, s).

2- (3-Nitroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.88 (4H, s), 6.83 (1H, dd, J = 8.0, 1.5 Hz), 7.16-7.22 (4H, m), 7.23-7.30 (2H, m ), 7.45 (1H, ddd, J = 8.2, 2.2, 1.0Hz), 7.53 (1H, t, J = 8.1Hz), 7.79 (1H, ddd, J = 8.1, 2.2, 1.0Hz), 7.85 (1H, d, J = 8.0Hz), 7.99 (1H, t, J = 2.2Hz), 9.69 (1H, s), 13.10 (1H, s).

2- (2-Nitroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.89 (4H, s), 6.99 (1H, dd, J = 8.2, 1.5Hz), 7.04-7.08 (1H, m), 7.15-7.31 (7H, m ), 7.51-7.55 (1H, m), 7.89 (1H, d, J = 8.2Hz), 8.11 (1H, dd, J = 8.4,1.6Hz), 11.06 (1H, s), 13.26 (1H, s) .

2- (2-Methylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.16 (3H, s), 2.74-2.86 (4H, m), 6.62-6.70 (2H, m), 7.00-7.10 (2H, m), 7.12-7.21 (4H, m), 7.22-7.30 (3H, m), 7.80 (1H, d, J = 8.0Hz), 9.48 (1H, s), 12.75-13.00 (1H, broad).

2- (4-Methoxyanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.72-2.86 (4H, m), 3.76 (3H, s), 6.59 (1H, dd, J = 8.2, 1.3 Hz), 6.69 (1H, d, J = 1.3Hz), 6.88-6.94 (2H, m), 6.99-7.05 (2H, m), 7.12-7.30 (5H, m), 7.77 (1H, d, J = 8.2Hz), 9.41 (1H, s) , 12.60-13.00 (1H, broad).

2- (3-Methoxyanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.84 (4H, s), 3.74 (3H, s), 6.59-6.76 (4H, m), 7.06 (1H, s), 7.15-7.30 (6H, m ), 7.81 (1H, d, J = 8.3Hz), 9.58 (1H, s), 12.93 (1H, s).

2-anilino-4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.89 (4H, m), 6.69 (1H, dd, J = 8.2, 1.3 Hz), 6.95 (1H, s), 7.00-7.08 (3H, m ), 7.14-7.34 (7H, m), 7.81 (1H, d, J = 8.2Hz), 9.60 (1H, s), 12.80-13.05 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、１−ヨード−３，４−メチレンジオキシベンゼン0.14g、炭酸セシウム0.22g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、トリス（ジベンジリデンアセトン）ジパラジウム（０）3mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；80-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−フェネチル安息香酸12mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.74-2.86(4H,m),6.03(2H,s),6.54(1H,dd,J=8.1,2.1Hz),6.61(1H,dd,J=8.1,1.5Hz),6.74(2H,d,J=2.1Hz),6.86(1H,d,J=8.1Hz),7.13-7.20(3H,m),7.22-7.29(2H,m),7.77(1H,d,J=8.1Hz),9.40(1H,s),12.70-12.95(1H,broad).Example 101

tert-Butyl-2-amino-4-phenethylbenzoate 0.10 g in toluene 3.0 mL solution, 1-iodo-3,4-methylenedioxybenzene 0.14 g, cesium carbonate 0.22 g, tris (dibenzylideneacetone) dipalladium (0) 3 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 8 mg were added, and the mixture was stirred at 110 ° C. for 24 hours. After cooling the reaction mixture to room temperature, 3 mg of tris (dibenzylideneacetone) dipalladium (0) and 8 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added, and the mixture was stirred at 110 ° C. for 24 hours. did. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flash Tube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 2-((benzo-1,3-dioxole). -5-yl) amino) -4-phenethylbenzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2-((benzo-1,3-dioxol-5-yl) amino) -4-phenethylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 80-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((benzo 12 mg of -1,3-dioxol-5-yl) amino) -4-phenethylbenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.74-2.86 (4H, m), 6.03 (2H, s), 6.54 (1H, dd, J = 8.1, 2.1 Hz), 6.61 (1H, dd, J = 8.1,1.5Hz), 6.74 (2H, d, J = 2.1Hz), 6.86 (1H, d, J = 8.1Hz), 7.13-7.20 (3H, m), 7.22-7.29 (2H, m), 7.77 (1H, d, J = 8.1Hz), 9.40 (1H, s), 12.70-12.95 (1H, broad).

Examples 102, 103
In the same manner as in Example 101, the compounds shown in Table 19 were obtained.

2-((3-Hydroxyphenyl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.89 (4H, m), 6.45 (1H, dd, J = 8.1, 1.7 Hz), 6.47-6.52 (1H, m), 6.57-6.60 (1H , m), 6.66 (1H, dd, J = 8.3, 1.2Hz), 7.06 (1H, s), 7.09 (1H, t, J = 7.9Hz), 7.15-7.28 (5H, m), 7.79 (1H, d, J = 8.2 Hz), 9.43 (1H, s), 9.55 (1H, s), 12.80-13.05 (1H, broad).

2-((4-Acetylphenyl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.52 (3H, s), 2.90 (4H, s), 6.86 (1H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.6 Hz) 7.16-7.25 (4H, m), 7.26-7.32 (2H, m), 7.82-7.90 (3H, m), 9.79 (1H, s), 12.95-13.30 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3mgおよび炭酸セシウム0.22gのトルエン3.0mL懸濁液に、５−ブロモベンゾフラン0.19gを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）3mgを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.0mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）3mgを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾフラン−５−イル）アミノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾフラン−５−イル）アミノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸3.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル：酢酸＝３０：1０：１］で精製し、白色固体の２−（（ベンゾフラン−５−イル）アミノ）−４−フェネチル安息香酸21mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.73-2.85(4H,m),6.63(1H,dd,J=8.2,1.2Hz),6.78(1H,s),6.92(1H,dd,J=2.2,0.8Hz),7.03(1H,dd,J=8.7,2.2Hz),7.11-7.22(3H,m),7.22-7.28(2H,m),7.38(1H,d,J=2.0Hz),7.55(1H,d,J=8.7Hz),7.80(1H,d,J=8.2Hz),8.00(1H,d,J=2.0Hz),9.53-9.63(1H,broad),12.76-12.92(1H,broad).Example 104

tert-butyl 2-amino-4-phenethylbenzoate 0.10 g, 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl 8 mg, tris (dibenzylideneacetone) dipalladium (0) 3 mg and carbonic acid To a suspension of cesium 0.22 g in toluene 3.0 mL, 5-bromobenzofuran 0.19 g was added and heated to reflux for 24 hours. After cooling the reaction mixture to room temperature, 8 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and 3 mg of tris (dibenzylideneacetone) dipalladium (0) were added, and the mixture was heated to reflux for 24 hours. After the reaction mixture was cooled to room temperature, 8.0 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and 3 mg of tris (dibenzylideneacetone) dipalladium (0) were added, and the mixture was heated to reflux for 24 hours. . The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 20: 1], and tert-butyl = 2-((benzofuran-5-yl) amino. ) -4-phenethylbenzoate was obtained.
To the obtained tert-butyl = 2-((benzofuran-5-yl) amino) -4-phenethylbenzoate, 3.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [Triconex, Flash Tube 2008, eluent; hexane: ethyl acetate: acetic acid = 30: 10: 1], and a white solid 21 mg of 2-((benzofuran-5-yl) amino) -4-phenethylbenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.73-2.85 (4H, m), 6.63 (1H, dd, J = 8.2, 1.2 Hz), 6.78 (1H, s), 6.92 (1H, dd, J = 2.2,0.8Hz), 7.03 (1H, dd, J = 8.7,2.2Hz), 7.11-7.22 (3H, m), 7.22-7.28 (2H, m), 7.38 (1H, d, J = 2.0Hz) , 7.55 (1H, d, J = 8.7Hz), 7.80 (1H, d, J = 8.2Hz), 8.00 (1H, d, J = 2.0Hz), 9.53-9.63 (1H, broad), 12.76-12.92 ( 1H, broad).

実施例１０４と同様にして、以下の化合物を得た。
２−（（ベンゾチオフェン−５−イル）アミノ）−４−フェネチル安息香酸
¹H-NMR(DMSO-d₆)δ値：2.76-2.88(4H,m),6.67(1H,d,J=7.3Hz),6.95(1H,s),7.10(1H,dd,J=8.7,2.0Hz),7.13-7.29(5H,m),7.38(1H,d,J=5.4Hz),7.63(1H,d,J=2.0Hz),7.77(1H,d,J=5.4Hz),7.82(1H,d,J=8.1Hz),7.92(1H,d,J=8.7Hz),9.67-9.74(1H,broad).Example 105

In the same manner as in Example 104, the following compound was obtained.
2-((Benzothiophen-5-yl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.76-2.88 (4H, m), 6.67 (1H, d, J = 7.3 Hz), 6.95 (1H, s), 7.10 (1H, dd, J = 8.7 , 2.0Hz), 7.13-7.29 (5H, m), 7.38 (1H, d, J = 5.4Hz), 7.63 (1H, d, J = 2.0Hz), 7.77 (1H, d, J = 5.4Hz), 7.82 (1H, d, J = 8.1Hz), 7.92 (1H, d, J = 8.7Hz), 9.67-9.74 (1H, broad).

２−（２−ニトロアニリノ）−４−フェネチル安息香酸20mgのメタノール2.0mLおよび酢酸エチル1.0mL混液に、5％パラジウム−炭素8mgを加え、水素雰囲気下、室温で3時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物にメタノールを加え、固形物をろ取し、白色固体の２−（（２−アミノフェニル）アミノ）−４−フェネチル安息香酸13mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.70-2.82(4H,m),4.60-5.00(2H,broad),6.48(1H,s),6.54-6.60(2H,m),6.79(1H,dd,J=8.1,1.5Hz),6.88-6.95(2H,m),7.12-7.19(3H,m),7.21-7.27(2H,m),7.77(1H,d,J=8.1Hz),9.02(1H,s).Example 106

To a mixed solution of 20 mg of 2- (2-nitroanilino) -4-phenethylbenzoic acid in 2.0 mL of methanol and 1.0 mL of ethyl acetate, 8 mg of 5% palladium-carbon was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and the solid was collected by filtration to obtain 13 mg of 2-((2-aminophenyl) amino) -4-phenethylbenzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.70-2.82 (4H, m), 4.60-5.00 (2H, broad), 6.48 (1H, s), 6.54-6.60 (2H, m), 6.79 (1H , dd, J = 8.1,1.5Hz), 6.88-6.95 (2H, m), 7.12-7.19 (3H, m), 7.21-7.27 (2H, m), 7.77 (1H, d, J = 8.1Hz), 9.02 (1H, s).

２−（３−ニトロアニリノ）−４−フェネチル安息香酸40mgのメタノール4.0mLおよび酢酸エチル2.0mL混液に、5％パラジウム−炭素20mgを加え、水素雰囲気下、室温で6時間攪拌した。不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物の酢酸エチル5mL溶液に、氷冷下で4.0mol/L塩化水素ジオキサン溶液0.028mLを加えた。固形物をろ取し、褐色固体の２−（（３−アミノフェニル）アミノ）−４−フェネチル安息香酸塩酸塩26mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.87(4H,s),6.75(1H,dd,J=8.1,1.2Hz),6.88(1H,d,J=7.6Hz),6.95(1H,d,J=8.1Hz),7.10-7.35(8H,m),7.83(1H,d,J=8.1Hz),9.68(1H,s).Example 107

To a mixed solution of methanol (4.0 mL) and ethyl acetate (2.0 mL) of 2- (3-nitroanilino) -4-phenethylbenzoic acid (40 mg), 5% palladium-carbon (20 mg) was added, and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To a 5 mL solution of the obtained residue in ethyl acetate, 0.028 mL of 4.0 mol / L hydrogen chloride dioxane solution was added under ice cooling. The solid was collected by filtration to obtain 26 mg of 2-((3-aminophenyl) amino) -4-phenethylbenzoic acid hydrochloride as a brown solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.87 (4H, s), 6.75 (1H, dd, J = 8.1, 1.2 Hz), 6.88 (1H, d, J = 7.6 Hz), 6.95 (1H, d, J = 8.1Hz), 7.10-7.35 (8H, m), 7.83 (1H, d, J = 8.1Hz), 9.68 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.10g、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル2.3mg、酢酸パラジウム0.8mgおよび炭酸セシウム0.24gのトルエン3.0mL懸濁液に、ヨードベンゼン0.10mLを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル2.3mgおよび酢酸パラジウム0.8mgを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、ｔｅｒｔ−ブチル＝２−アニリノ−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−アニリノ−４−フェニルベンゾアートのトリフルオロ酢酸3.0mL溶液を室温で3時間攪拌した。反応混合物の溶媒を減圧下で留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル：酢酸＝３０：1０：１］で精製し、淡黄色固体の２−アニリノ−４−フェニル安息香酸8mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.06-7.12(2H,m),7.32-7.48(8H,m),7.58-7.60(2H,m),7.99(1H,d,J=8.3Hz),9.71(1H,s),13.10-13.14(1H,broad).Example 108

tert-Butyl-2-amino-4-phenylbenzoate 0.10 g, rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl 2.3 mg, palladium acetate 0.8 mg and cesium carbonate 0.24 g of toluene To the 3.0 mL suspension, 0.10 mL of iodobenzene was added and heated to reflux for 24 hours. After the reaction mixture was cooled to room temperature, rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (2.3 mg) and palladium acetate (0.8 mg) were added, and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 20: 1] to obtain tert-butyl = 2-anilino-4-phenylbenzoate. It was.
The resulting solution of tert-butyl = 2-anilino-4-phenylbenzoate in 3.0 mL of trifluoroacetic acid was stirred at room temperature for 3 hours. The solvent of the reaction mixture was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate: acetic acid = 30: 10: 1]. As a result, 8 mg of 2-anilino-4-phenylbenzoic acid was obtained as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.06-7.12 (2H, m), 7.32-7.48 (8H, m), 7.58-7.60 (2H, m), 7.99 (1H, d, J = 8.3Hz ), 9.71 (1H, s), 13.10-13.14 (1H, broad).

Examples 109-115
In the same manner as in Example 108, the compounds shown in Table 20 were obtained.

2- (2,4-Difluoroanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.05-7.16 (3H, m), 7.38-7.47 (4H, m), 7.56-7.66 (3H, m), 7.99 (1H, d, J = 8.1 Hz) ), 9.56 (1H, s), 13.19-13.25 (1H, broad).

2- (3-Fluoro-4-methylanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.21 (3H, s), 7.08-7.15 (3H, m), 7.26 (1H, t, J = 8.5 Hz), 7.38-7.48 (4H, m), 7.60 (2H, d, J = 7.3Hz), 7.99 (1H, d, J = 8.3Hz), 9.66 (1H, s), 13.11-13.19 (1H, broad).

2- (3-Nitroanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.25 (1H, d, J = 8.3 Hz), 7.40-7.50 (3H, m), 7.59-7.67 (4H, m), 7.77 (1H, dd, J = 7.9,1.8Hz), 7.83 (1H, dd, J = 8.0,2.0Hz), 8.04 (1H, d, J = 8.3Hz), 8.11 (1H, s), 9.79 (1H, s), 13.23-13.35 (1H, broad).

2- (2-Nitroanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.11 (1H, t, J = 7.6 Hz), 7.38 (1H, dd, J = 8.5, 1.5 Hz), 7.40-7.44 (1H, m), 7.48 ( 2H, t, J = 7.4Hz), 7.64-7.69 (3H, m), 7.73 (1H, s), 7.79 (1H, d, J = 8.6Hz), 8.06 (1H, d, J = 8.3Hz), 8.15 (1H, dd, J = 8.4,1.3Hz), 11.14 (1H, s), 13.37-13.51 (1H, broad).

2-((4-Acetylphenyl) amino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.52 (3H, s), 7.26 (1H, dd, J = 8.3, 1.6 Hz), 7.37-7.44 (3H, m), 7.49 (2H, t, J = 7.5Hz), 7.67-7.69 (3H, m), 7.94 (2H, d, J = 8.5Hz), 8.04 (1H, d, J = 8.3Hz), 9.89 (1H, s), 13.27-13.36 (1H , broad).

2- (2-Methylanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.24 (3H, s), 7.01-7.11 (3H, m), 7.25 (1H, t, J = 7.1 Hz), 7.32-7.46 (5H, m), 7.52-7.54 (2H, m), 7.99 (1H, d, J = 8.3Hz), 9.59 (1H, s), 13.05-13.13 (1H, broad).

2- (3-Methoxyanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.32 (3H, s), 6.67 (1H, dd, J = 8.3, 2.3 Hz), 6.85-6.87 (1H, m), 6.91-6.93 (1H, m ), 7.07-7.09 (1H, m), 7.28 (1H, t, J = 8.2Hz), 7.38-7.48 (4H, m), 7.59 (2H, d, J = 7.8Hz), 7.99 (1H, d, J = 8.3Hz), 9.68 (1H, s), 13.08-13.18 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.10g、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル2.3mg、酢酸パラジウム0.8mgおよび炭酸セシウム0.24gのトルエン3.0mL懸濁液に、２，３−ジヒドロ−６−ヨードベンゾ［１，４］ジオキシン0.24gを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、ｒａｃ−２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル2.3mgおよび酢酸パラジウム0.8mgを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）アミノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）アミノ）−４−フェニルベンゾアートのトリフルオロ酢酸3.0mL溶液を室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；70-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の２−（（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）アミノ）−４−フェニル安息香酸5mgを得た。
¹H-NMR(DMSO-d₆)δ値：4.24(4H,s),6.79-6.82(2H,m),6.88(1H,d,J=8.6Hz),6.99(1H,dd,J=8.3,1.7Hz),7.21(1H,s),7.37-7.41(1H,m),7.43-7.47(2H,m),7.53-7.55(2H,m),7.95(1H,d,J=8.3Hz),9.46-9.54(1H,broad),12.94-13.07(1H,broad).Example 116

tert-Butyl-2-amino-4-phenylbenzoate 0.10 g, rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl 2.3 mg, palladium acetate 0.8 mg and cesium carbonate 0.24 g of toluene To the 3.0 mL suspension, 0.24 g of 2,3-dihydro-6-iodobenzo [1,4] dioxin was added and heated to reflux for 24 hours. After the reaction mixture was cooled to room temperature, rac-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (2.3 mg) and palladium acetate (0.8 mg) were added, and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((2,3-dihydrobenzo [ 1,4] dioxin-6-yl) amino) -4-phenylbenzoate was obtained.
The obtained tert-butyl = 2-((2,3-dihydrobenzo [1,4] dioxin-6-yl) amino) -4-phenylbenzoate solution in 3.0 mL of trifluoroacetic acid was stirred at room temperature for 3 hours. . The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 70-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((2 , 3-Dihydrobenzo [1,4] dioxin-6-yl) amino) -4-phenylbenzoic acid 5 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 4.24 (4H, s), 6.79-6.82 (2H, m), 6.88 (1H, d, J = 8.6 Hz), 6.99 (1H, dd, J = 8.3) , 1.7Hz), 7.21 (1H, s), 7.37-7.41 (1H, m), 7.43-7.47 (2H, m), 7.53-7.55 (2H, m), 7.95 (1H, d, J = 8.3Hz) , 9.46-9.54 (1H, broad), 12.94-13.07 (1H, broad).

Examples 117 and 118
In the same manner as in Example 116, the compounds shown in Table 21 were obtained.

4-Phenyl-2- (4- (1H-pyrazol-1-yl) anilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.53 (1H, t, J = 2.1 Hz), 7.10 (1H, dd, J = 8.3, 1.7 Hz), 7.38-7.48 (6H, m), 7.60- 7.63 (2H, m), 7.73 (1H, d, J = 1.7Hz), 7.83-7.85 (2H, m), 8.00 (1H, d, J = 8.3Hz), 8.46 (1H, d, J = 2.4Hz ), 9.75 (1H, s), 13.12-13.20 (1H, s).

2-((Benzo-1,3-dioxol-5-yl) amino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.04 (2H, s), 6.79 (1H, dd, J = 8.3, 2.1 Hz), 6.93 (1H, d, J = 8.3 Hz), 6.96 (1H, d, J = 2.1Hz), 6.99 (1H, dd, J = 8.3,1.6Hz), 7.17 (1H, s), 7.37-7.40 (1H, m), 7.45 (2H, t, J = 7.3Hz), 7.53-7.55 (2H, m), 7.95 (1H, d, J = 8.3Hz), 9.48-9.56 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.10g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3mgおよび炭酸セシウム0.24gのトルエン3.0mL懸濁液に、５−ブロモベンゾフラン0.18gを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）3mgを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）3mgを加え、24時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝３０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾフラン−５−イル）アミノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾフラン−５−イル）アミノ）−４−フェニルベンゾアートのトリフルオロ酢酸3.0mL溶液を室温で3時間攪拌した。反応混合物の溶媒を減圧下で留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル：酢酸＝３０：1０：１］で精製し、２−（（ベンゾフラン−５−イル）アミノ）−４−フェニル安息香酸42mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.95(1H,dd,J=2.2,0.7Hz),7.01(1H,dd,J=8.3,1.7Hz),7.23(1H,d,J=1.4Hz),7.28(1H,dd,J=8.8,2.2Hz),7.34-7.46(3H,m),7.52-7.54(2H,m),7.61-7.64(2H,m),7.98(1H,d,J=8.3Hz),8.01(1H,d,J=2.2Hz),9.64-9.76(1H,broad),12.88-13.20(1H,broad).Example 119

tert-Butyl-2-amino-4-phenylbenzoate 0.10 g, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9 mg, tris (dibenzylideneacetone) dipalladium (0) 3 mg and carbonic acid To a suspension of cesium 0.24 g in toluene 3.0 mL, 5-bromobenzofuran 0.18 g was added and heated to reflux for 24 hours. After cooling the reaction mixture to room temperature, 9 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and 3 mg of tris (dibenzylideneacetone) dipalladium (0) were added, and the mixture was heated to reflux for 24 hours. After cooling the reaction mixture to room temperature, 9 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and 3 mg of tris (dibenzylideneacetone) dipalladium (0) were added, and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 30: 1], and tert-butyl = 2-((benzofuran-5-yl) amino. ) -4-Phenylbenzoate was obtained.
The resulting tert-butyl = 2-((benzofuran-5-yl) amino) -4-phenylbenzoate solution in 3.0 mL of trifluoroacetic acid was stirred at room temperature for 3 hours. The solvent of the reaction mixture was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate: acetic acid = 30: 10: 1]. , 2-((benzofuran-5-yl) amino) -4-phenylbenzoic acid 42 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.95 (1H, dd, J = 2.2,0.7 Hz), 7.01 (1H, dd, J = 8.3,1.7 Hz), 7.23 (1H, d, J = 1.4 Hz), 7.28 (1H, dd, J = 8.8,2.2Hz), 7.34-7.46 (3H, m), 7.52-7.54 (2H, m), 7.61-7.64 (2H, m), 7.98 (1H, d, J = 8.3Hz), 8.01 (1H, d, J = 2.2Hz), 9.64-9.76 (1H, broad), 12.88-13.20 (1H, broad).

実施例１１９と同様にして、以下の化合物を得た。
２−（（ベンゾチオフェン−５−イル）アミノ）−４−フェニル安息香酸
¹H-NMR(DMSO-d₆)δ値：7.06(1H,dd,J=8.3,1.7Hz),7.35-7.45(6H,m),7.57(2H,d,J=7.3Hz),7.78(1H,d,J=5.4Hz),7.84(1H,d,J=1.9Hz),8.00(2H,d,J=8.3Hz),9.77-9.95(1H, broad).Example 120

In the same manner as in Example 119, the following compound was obtained.
2-((Benzothiophen-5-yl) amino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.06 (1H, dd, J = 8.3,1.7 Hz), 7.35-7.45 (6H, m), 7.57 (2H, d, J = 7.3 Hz), 7.78 ( 1H, d, J = 5.4Hz), 7.84 (1H, d, J = 1.9Hz), 8.00 (2H, d, J = 8.3Hz), 9.77-9.95 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.20g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル17mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）7mg、酢酸パラジウム2mgおよび炭酸セシウム0.48gのトルエン3.0mL懸濁液に、ｔｅｒｔ−ブチル＝５−ブロモインドール−１−カルボキシラート0.55gを加え、8時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（１−（ｔｅｒｔ−ブトキシカルボニル）−１Ｈ−インドール−５−イル）アミノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（１−（ｔｅｒｔ−ブトキシカルボニル）−１Ｈ−インドール−５−イル）アミノ）−４−フェニルベンゾアートのトリフルオロ酢酸5mL溶液を室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の２−（（１Ｈ−インドール−５−イル）アミノ）−４−フェニル安息香酸8mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.42(1H,s),6.93(1H,dd,J=8.4,1.3Hz),7.05(1H,dd,J=8.6,1.7Hz),7.12(1H,s),7.32-7.48(8H,m),7.95(1H,d,J=8.3Hz),9.60(1H,s),11.18(1H,s),12.77-13.01(1H,broad).Example 121

tert-Butyl-2-amino-4-phenylbenzoate 0.20 g, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 17 mg, tris (dibenzylideneacetone) dipalladium (0) 7 mg, acetic acid To a suspension of palladium (2 mg) and cesium carbonate (0.48 g) in toluene (3.0 mL) was added tert-butyl = 5-bromoindole-1-carboxylate (0.55 g), and the mixture was heated to reflux for 8 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 20: 1], and tert-butyl = 2-((1- (tert-butoxycarbonyl ) -1H-Indol-5-yl) amino) -4-phenylbenzoate was obtained.
The obtained tert-butyl = 2-((1- (tert-butoxycarbonyl) -1H-indol-5-yl) amino) -4-phenylbenzoate in 5 mL of trifluoroacetic acid was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 50-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((1H -Indol-5-yl) amino) -4-phenylbenzoic acid 8 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.42 (1H, s), 6.93 (1H, dd, J = 8.4, 1.3 Hz), 7.05 (1H, dd, J = 8.6, 1.7 Hz), 7.12 ( 1H, s), 7.32-7.48 (8H, m), 7.95 (1H, d, J = 8.3Hz), 9.60 (1H, s), 11.18 (1H, s), 12.77-13.01 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.20g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル17mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）7mg、酢酸パラジウム2mgおよび炭酸セシウム0.48gのトルエン3.0mL懸濁液に、３−ヨードフェノール0.41gを加え、12時間加熱還流した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝６：１］で精製し、ｔｅｒｔ−ブチル＝２−（（３−ヒドロキシフェニル）アミノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（３−ヒドロキシフェニル）アミノ）−４−フェニルベンゾアートのトリフルオロ酢酸5.0mL溶液を室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物に、ヘキサンおよびジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（（３−ヒドロキシフェニル）アミノ）−４−フェニル安息香酸15mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.49(1H,dd,J=8.2,1.6Hz),6.71-6.74(2H,m),7.07(1H,dd,J=8.3,1.5Hz),7.16(1H,t,J=7.9Hz),7.39-7.42(1H,m),7.45-7.49(3H,m),7.61(2H,d,J=7.3Hz),7.98(1H,d,J=8.3Hz),9.45-9.52(1H,broad),9.65(1H,s),13.05-13.17(1H,broad).Example 122

tert-Butyl-2-amino-4-phenylbenzoate 0.20 g, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 17 mg, tris (dibenzylideneacetone) dipalladium (0) 7 mg, acetic acid To a 3.0 mL suspension of toluene in 2 mg palladium and 0.48 g cesium carbonate, 0.41 g 3-iodophenol was added and heated to reflux for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 6: 1], and tert-butyl = 2-((3-hydroxyphenyl ) Amino) -4-phenylbenzoate was obtained.
The obtained tert-butyl = 2-((3-hydroxyphenyl) amino) -4-phenylbenzoate solution in 5.0 mL of trifluoroacetic acid was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, hexane and diisopropyl ether were added to the obtained residue, the solid was collected by filtration, and 2-((3-hydroxyphenyl) amino) -4-phenylbenzoic acid as a yellow solid 15 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.49 (1H, dd, J = 8.2, 1.6 Hz), 6.71-6.74 (2H, m), 7.07 (1H, dd, J = 8.3, 1.5 Hz), 7.16 (1H, t, J = 7.9Hz), 7.39-7.42 (1H, m), 7.45-7.49 (3H, m), 7.61 (2H, d, J = 7.3Hz), 7.98 (1H, d, J = 8.3Hz), 9.45-9.52 (1H, broad), 9.65 (1H, s), 13.05-13.17 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.20gのトルエン4.0mL溶液に、室温でｔｅｒｔ−ブチル＝５−ブロモ−１Ｈ−インドール−１−カルボキシラート0.29g、炭酸セシウム0.55g、トリス（ジベンジリデンアセトン）ジパラジウム（０）6mg、酢酸パラジウム3mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル16mgを加え、窒素雰囲気下、8時間加熱還流した。反応混合物を室温まで冷却した後、トリス（ジベンジリデンアセトン）ジパラジウム（０）6mg、酢酸パラジウム3mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル16mgを加え、窒素雰囲気下、10時間加熱還流した。反応混合物を室温まで冷却した後、水を加え、不溶物をろ去した。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（１−（ｔｅｒｔ−ブトキシカルボニル）−１Ｈ−インドール−５−イル）アミノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（１−（ｔｅｒｔ−ブトキシカルボニル）−１Ｈ−インドール−５−イル）アミノ）−４−フェネチルベンゾアートのトリフルオロ酢酸3.0mL溶液を室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；60-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（（１Ｈ−インドール−５−イル）アミノ）−４−フェネチル安息香酸25mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.72-2.80(4H,m),6.40(1H,s),6.55(1H,d,J=8.0Hz),6.70(1H,s),6.85(1H,dd,J=8.4,2.0Hz),7.12-7.29(6H,m),7.35-7.39(2H,m),7.77(1H,d,J=8.4Hz),9.46-9.54(1H,broad),11.10(1H,s),12.60-12.80(1H,broad).Example 123

To a 4.0 mL toluene solution of 0.20 g of tert-butyl 2-amino-4-phenethylbenzoate, 0.29 g of tert-butyl = 5-bromo-1H-indole-1-carboxylate, 0.55 g of cesium carbonate, tris ( Dibenzylideneacetone) dipalladium (0) 6 mg, palladium acetate 3 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 16 mg were added, and the mixture was heated to reflux for 8 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 6 mg of tris (dibenzylideneacetone) dipalladium (0), 3 mg of palladium acetate and 16 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added, and nitrogen atmosphere was added. Under reflux for 10 hours. The reaction mixture was cooled to room temperature, water was added, and the insoluble material was removed by filtration. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((1- (tert-butoxycarbonyl ) -1H-Indol-5-yl) amino) -4-phenethylbenzoate was obtained.
The resulting tert-butyl = 2-((1- (tert-butoxycarbonyl) -1H-indol-5-yl) amino) -4-phenethylbenzoate solution in 3.0 mL of trifluoroacetic acid was stirred at room temperature for 1 hour. . The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 60-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-(( 25 mg of 1H-indol-5-yl) amino) -4-phenethylbenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.72-2.80 (4H, m), 6.40 (1H, s), 6.55 (1H, d, J = 8.0 Hz), 6.70 (1H, s), 6.85 ( 1H, dd, J = 8.4,2.0Hz), 7.12-7.29 (6H, m), 7.35-7.39 (2H, m), 7.77 (1H, d, J = 8.4Hz), 9.46-9.54 (1H, broad) , 11.10 (1H, s), 12.60-12.80 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.20gのトルエン3.0mL溶液に、室温でビニルシクロヘキサン0.15mL、炭酸セシウム0.36g、テトラブチルアンモニウムブロミド53mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）86mgを加え、110℃で22時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−シクロヘキシルビニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（（Ｅ）−２−シクロヘキシルビニル）−２−（４−フルオロアニリノ）ベンゾアートのトリフルオロ酢酸15mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、淡黄色固体の４−（（Ｅ）−２−シクロヘキシルビニル）−２−（４−フルオロアニリノ）安息香酸34mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.08-1.31(5H,m),1.59-1.78(5H,m),2.05-2.14(1H,m),6.26(2H,d,J=2.4Hz),6.87(1H,dd,J=8.4,0.7Hz),6.97(1H,s),7.17-7.31(4H,m),7.81(1H,d,J=8.4Hz),9.49-9.61(1H,broad),12.86-13.02(1H,broad).Example 124

To a solution of 0.20 g of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate in 3.0 mL of toluene, 0.15 mL of vinylcyclohexane, 0.36 g of cesium carbonate, 53 mg of tetrabutylammonium bromide and bis (polymer-supported bis ( Acetate) triphenylphosphine palladium (II) 86 mg was added and stirred at 110 ° C. for 22 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 4-((E) -2-cyclohexylvinyl. ) -2- (4-Fluoroanilino) benzoate was obtained.
The obtained tert-butyl = 4-((E) -2-cyclohexylvinyl) -2- (4-fluoroanilino) benzoate in 15 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain 34 mg of 4-((E) -2-cyclohexylvinyl) -2- (4-fluoroanilino) benzoic acid as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.08-1.31 (5H, m), 1.59-1.78 (5H, m), 2.05-2.14 (1H, m), 6.26 (2H, d, J = 2.4Hz ), 6.87 (1H, dd, J = 8.4, 0.7Hz), 6.97 (1H, s), 7.17-7.31 (4H, m), 7.81 (1H, d, J = 8.4Hz), 9.49-9.61 (1H, broad), 12.86-13.02 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.20gのトルエン3.0mL溶液に、室温でアリルシクロヘキサン0.17mL、炭酸セシウム0.36g、テトラブチルアンモニウムブロミド53mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）86mgを加え、110℃で22時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−３−シクロヘキシル−１−プロペニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（（Ｅ）−３−シクロヘキシル−１−プロペニル）−２−（４−フルオロアニリノ）ベンゾアートのトリフルオロ酢酸15mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；70-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の４−（（Ｅ）−３−シクロヘキシル−１−プロペニル）−２−（４−フルオロアニリノ）安息香酸23mgを得た。
¹H-NMR(DMSO-d₆)δ値：0.82-0.96(2H,m),1.04-1.25(3H,m),1.30-1.41(1H,m),1.55-1.71(5H,m),1.99-2.09(2H,m),6.22-6.35(2H,m),6.87(1H,d,J=8.3Hz),6.96(1H,s),7.17-7.33(4H,m),7.82(1H,d,J=8.3Hz),9.56(1H,s),12.94(1H,s).Example 125

A solution of 0.20 g of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate in 3.0 mL of toluene was added at room temperature to 0.17 mL of allylcyclohexane, 0.36 g of cesium carbonate, 53 mg of tetrabutylammonium bromide and bis ( Acetate) triphenylphosphine palladium (II) 86 mg was added and stirred at 110 ° C. for 22 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 4-((E) -3-cyclohexyl- 1-propenyl) -2- (4-fluoroanilino) benzoate was obtained.
The obtained tert-butyl = 4-((E) -3-cyclohexyl-1-propenyl) -2- (4-fluoroanilino) benzoate in 15 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 70-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 4-(( E) 23 mg of 3-cyclohexyl-1-propenyl) -2- (4-fluoroanilino) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 0.82-0.96 (2H, m), 1.04-1.25 (3H, m), 1.30-1.41 (1H, m), 1.55-1.71 (5H, m), 1.99 -2.09 (2H, m), 6.22-6.35 (2H, m), 6.87 (1H, d, J = 8.3Hz), 6.96 (1H, s), 7.17-7.33 (4H, m), 7.82 (1H, d , J = 8.3Hz), 9.56 (1H, s), 12.94 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.12gのトルエン3.0mL溶液に、室温で３−ヨードフェノール0.17g、炭酸セシウム0.25g、テトラブチルアンモニウムブロミド37mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）58mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−ヒドロキシフェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−ヒドロキシフェニル）ビニル）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；40-90％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−ヒドロキシフェニル）ビニル）安息香酸27mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.69(1H,d,J=8.0Hz),6.97(1H,s),7.02-7.26(8H,m),7.30-7.36(2H,m),7.88(1H,d,J=8.3Hz),9.41(1H,s),9.60(1H,s),12.98(1H,s).Example 126

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate 0.12 g in toluene (3.0 mL), 3-iodophenol 0.17 g, cesium carbonate 0.25 g, tetrabutylammonium bromide 37 mg and polymer supported at room temperature 58 mg of bis (acetate) triphenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (3-hydroxyphenyl) vinyl) benzoate was obtained.
The obtained tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (3-hydroxyphenyl) vinyl) benzoate in 10 mL of trifluoroacetic acid was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reversed-phase silica gel column chromatography [eluent: 40-90% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4 -Fluoroanilino) -4-((E) -2- (3-hydroxyphenyl) vinyl) benzoic acid 27 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.69 (1H, d, J = 8.0 Hz), 6.97 (1H, s), 7.02-7.26 (8H, m), 7.30-7.36 (2H, m), 7.88 (1H, d, J = 8.3Hz), 9.41 (1H, s), 9.60 (1H, s), 12.98 (1H, s).

Examples 127-130
In the same manner as in Example 126, the compounds shown in Table 22 were obtained.

2- (4-Fluoroanilino) -4-((E) -2- (4-hydroxyphenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.75 (2H, d, J = 8.6Hz), 6.95 (1H, d, J = 16.1Hz), 7.04 (1H, d, J = 8.3Hz), 7.12 -7.37 (6H, m), 7.44 (2H, d, J = 8.6Hz), 7.86 (1H, d, J = 8.3Hz), 9.54-9.75 (2H, m).

2- (4-Fluoroanilino) -4-((E) -2- (4-methoxyphenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.77 (3H, s), 6.93 (2H, d, J = 8.8 Hz), 7.01-7.10 (2H, m), 7.14-7.27 (4H, m), 7.30-7.38 (2H, m), 7.56 (2H, d, J = 8.8Hz), 7.87 (1H, d, J = 8.5Hz), 9.60 (1H, s), 12.87-13.08 (1H, broad).

2- (4-Fluoroanilino) -4-((E) -2- (2-hydroxyphenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.79 (1H, t, J = 7.6 Hz), 6.85 (1H, d, J = 7.8 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.07 -7.17 (3H, m), 7.20-7.27 (2H, m), 7.31-7.37 (2H, m), 7.41 (1H, d, J = 16.6Hz), 7.58 (1H, d, J = 7.6Hz), 7.88 (1H, d, J = 8.5Hz), 9.58 (1H, s), 9.80 (1H, s), 12.97 (1H, s).

2- (4-Fluoroanilino) -4-((E) -2- (4- (1H-pyrazol-1-yl) phenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.56 (1H, t, J = 2.1 Hz), 7.12 (1H, dd, J = 8.7, 1.1 Hz), 7.21-7.28 (5H, m), 7.32 7.36 (2H, m), 7.73-7.76 (3H, m), 7.85 (2H, d, J = 8.8Hz), 7.90 (1H, d, J = 8.3Hz), 8.54 (1H, d, J = 2.4Hz) ), 9.52-9.78 (1H, broad).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.12gのトルエン3.0mL溶液に、室温で２，３−ジヒドロ−６−ヨードベンゾ［１，４］ジオキシン0.20g、炭酸セシウム0.25g、テトラブチルアンモニウムブロミド37mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）58mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で1時間攪拌した。減圧下で溶媒を留去し、淡黄色固体の４−（（Ｅ）−２−（２，３−ジヒドロベンゾ［１，４］ジオキシン−６−イル）ビニル）−２−（４−フルオロアニリノ）安息香酸17mgを得た。
¹H-NMR(DMSO-d₆)δ値：4.24(4H,s),6.83(1H,d,J=8.3Hz),7.00-7.15(6H,m),7.20-7.26(2H,m),7.29-7.36(2H,m),7.86(1H,d,J=8.3Hz),9.60(1H,s),12.83-13.08(1H,broad).Example 131

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate 0.12 g in a toluene 3.0 mL solution at room temperature with 2,3-dihydro-6-iodobenzo [1,4] dioxin 0.20 g, cesium carbonate 0.25 g, tetrabutylammonium bromide 37 mg and polymer-supported bis (acetate) triphenylphosphine palladium (II) 58 mg were added, and the mixture was stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 4-((E) -2- (2 , 3-Dihydrobenzo [1,4] dioxin-6-yl) vinyl) -2- (4-fluoroanilino) benzoate.
Trityl of tert-butyl 4-((E) -2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) vinyl) -2- (4-fluoroanilino) benzoate obtained A 10 mL solution of fluoroacetic acid was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and a pale yellow solid 4-((E) -2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) vinyl) -2- (4-fluoroani Reno) 17 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 4.24 (4H, s), 6.83 (1H, d, J = 8.3 Hz), 7.00-7.15 (6H, m), 7.20-7.26 (2H, m), 7.29-7.36 (2H, m), 7.86 (1H, d, J = 8.3Hz), 9.60 (1H, s), 12.83-13.08 (1H, broad).

Examples 132-136
In the same manner as in Example 131, the compounds shown in Table 23 were obtained.

2- (4-Fluoroanilino) -4-((E) -2- (4-fluorophenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.10 (1H, dd, J = 8.4,1.3 Hz), 7.13-7.28 (7H, m), 7.31-7.36 (2H, m), 7.65-7.70 (2H , m), 7.89 (1H, d, J = 8.4Hz), 9.60 (1H, s), 12.88-13.14 (1H, broad).

2- (4-Fluoroanilino) -4-((E) -2- (3-fluoro-4-methylphenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.23 (3H, s), 7.09 (1H, dd, J = 8.4, 1.5 Hz), 7.17-7.28 (6H, m), 7.31-7.35 (3H, m ), 7.44 (1H, d, J = 11.7Hz), 7.89 (1H, d, J = 8.4Hz), 9.59 (1H, s), 12.92-13.11 (1H, broad).

4-((E) -2- (2,4-difluorophenyl) vinyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.10-7.36 (10H, m), 7.84-7.91 (2H, m), 9.60 (1H, s).

2- (4-Fluoroanilino) -4-((E) -2- (2-methylphenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.38 (3H, s), 7.07 (1H, d, J = 16.1 Hz), 7.14-7.26 (7H, m), 7.31-7.37 (2H, m), 7.41 (1H, d, J = 16.1Hz), 7.67 (1H, t, J = 3.0Hz), 7.89 (1H, d, J = 8.3Hz), 9.61 (1H, s), 12.85-13.19 (1H, broad ).

4-((E) -2- (benzothiophen-3-yl) vinyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.20-7.51 (9H, m), 7.62 (1H, d, J = 16.4Hz), 7.91 (1H, d, J = 8.3Hz), 8.03 (1H, d, J = 7.6Hz), 8.11 (1H, s), 8.23 (1H, d, J = 8.0Hz), 9.53-9.74 (1H, broad), 12.87-13.20 (1H, broad).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.12gのトルエン3.0mL溶液に、室温で３−ヨードアニソール0.18g、炭酸セシウム0.25g、テトラブチルアンモニウムブロミド37mgおよびポリマー担持ビス（アセタート）トリフェニルホスフィンパラジウム（II）58mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−メトキシフェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−メトキシフェニル）ビニル）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物に、酢酸エチルおよび飽和チオ硫酸ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色固体の２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−メトキシフェニル）ビニル）安息香酸28mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.78(3H,s),6.85(1H,ddd,J=8.2,2.4,0.8Hz),7.11(1H,dd,J=8.5,1.5Hz),7.16-7.37(10H,m),7.89(1H,d,J=8.5Hz),9.61(1H,s),12.83-13.21(1H,broad).Example 137

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate 0.12 g in toluene 3.0 mL solution at room temperature 3-iodoanisole 0.18 g, cesium carbonate 0.25 g, tetrabutylammonium bromide 37 mg and polymer supported 58 mg of bis (acetate) triphenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (3-methoxyphenyl) vinyl) benzoate was obtained.
The obtained tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (3-methoxyphenyl) vinyl) benzoate solution in 10 mL of trifluoroacetic acid was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium thiosulfate solution were added to the obtained residue. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2- (4-fluoroanilino) -4-((E ) -2- (3-Methoxyphenyl) vinyl) benzoic acid 28 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.78 (3H, s), 6.85 (1H, ddd, J = 8.2, 2.4, 0.8 Hz), 7.11 (1H, dd, J = 8.5, 1.5 Hz), 7.16-7.37 (10H, m), 7.89 (1H, d, J = 8.5Hz), 9.61 (1H, s), 12.83-13.21 (1H, broad).

Examples 138-140
In the same manner as in Example 137, the compounds shown in Table 24 were obtained.

4-((E) -2- (4-acetylphenyl) vinyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.58 (3H, s), 7.15 (1H, dd, J = 8.5, 1.2 Hz), 7.21-7.27 (3H, m), 7.31-7.42 (4H, m ), 7.76 (2H, d, J = 8.3Hz), 7.91 (1H, d, J = 8.5Hz), 7.94 (2H, d, J = 8.3Hz), 9.61 (1H, s), 12.97-13.17 (1H , broad).

2- (4-Fluoroanilino) -4-((E) -2- (3-nitrophenyl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.66 (1H, t, J = 7.9 Hz), 7.15 (1H, dd, J = 8.3, 1.2 Hz), 7.21-7.30 (3H, m), 7.31 7.37 (2H, m), 7.42 (1H, d, J = 16.6Hz), 7.48 (1H, d, J = 16.6Hz), 7.92 (1H, d, J = 8.3Hz), 8.07-8.14 (2H, m ), 8.47 (1H, s), 9.54-9.79 (1H, broad).

4-((E) -2- (Benzo-1,3-dioxol-5-yl) vinyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.03 (2H, s), 6.90 (1H, d, J = 8.0 Hz), 7.03-7.09 (3H, m), 7.13-7.26 (4H, m), 7.30-7.36 (3H, m), 7.87 (1H, d, J = 8.3Hz), 9.44-9.76 (1H, broad), 12.76-13.14 (1H, broad).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で３−ブロモチオフェン90μL、炭酸セシウム0.31gおよび酢酸パラジウム11mgを加え、120℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（チオフェン−３−イル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（チオフェン−３−イル）ビニル）ベンゾアートのトリフルオロ酢酸15mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；70-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（チオフェン−３−イル）ビニル）安息香酸9mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.00-7.09(2H,m),7.13(1H,s),7.20-7.36(5H,m),7.50(1H,d,J=4.9Hz),7.56(1H,dd,J=4.9,2.8Hz),7.64(1H,d,J=2.8Hz),7.87(1H,d,J=8.3Hz),9.53-9.67(1H,broad),12.85-13.10(1H,broad).Example 141

tert-Butyl-2- (4-fluoroanilino) -4-vinylbenzoate 0.15 g of N, N-dimethylacetamide in 3.0 mL was charged with 90 μL of 3-bromothiophene, 0.31 g of cesium carbonate and 11 mg of palladium acetate at room temperature. In addition, the mixture was stirred at 120 ° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (thiophen-3-yl) vinyl) benzoate was obtained.
A solution of tert-butyl 2- (4-fluoroanilino) -4-((E) -2- (thiophen-3-yl) vinyl) benzoate obtained in 15 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. . The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 70-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4 -Fluoroanilino) -4-((E) -2- (thiophen-3-yl) vinyl) benzoic acid 9 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.00-7.09 (2H, m), 7.13 (1H, s), 7.20-7.36 (5H, m), 7.50 (1H, d, J = 4.9 Hz), 7.56 (1H, dd, J = 4.9,2.8Hz), 7.64 (1H, d, J = 2.8Hz), 7.87 (1H, d, J = 8.3Hz), 9.53-9.67 (1H, broad), 12.85-13.10 (1H, broad).

Examples 142, 143
In the same manner as in Example 141, the compounds shown in Table 25 were obtained.

2- (4-Fluoroanilino) -4-((E) -2- (1H-indol-4-yl) vinyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.85 (1H, s), 7.09 (1H, t, J = 7.7 Hz), 7.20-7.28 (5H, m), 7.32-7.39 (4H, m), 7.43 (1H, t, J = 2.8Hz), 7.59 (1H, d, J = 16.6Hz), 7.90 (1H, d, J = 8.3Hz), 9.62 (1H, s), 11.23 (1H, s), 12.89-13.07 (1H, broad).

4-((E) -2- (benzothiophen-5-yl) vinyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.13 (1H, dd, J = 8.3,1.1 Hz), 7.21-7.41 (7H, m), 7.44 (1H, d, J = 5.4 Hz), 7.68 ( 1H, dd, J = 8.7,0.9Hz), 7.78 (1H, d, J = 5.4Hz), 7.90 (1H, d, J = 8.3Hz), 7.98 (1H, d, J = 8.7Hz), 8.08 ( 1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で１−ブロモ−４−（トリフルオロメチル）ベンゼン0.14mL、炭酸セシウム0.31gおよび酢酸パラジウム11mgを加え、120℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−トリフルオロメチルフェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−トリフルオロメチルフェニル）ビニル）ベンゾアートのトリフルオロ酢酸15mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、淡黄色固体の２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−トリフルオロメチルフェニル）ビニル）安息香酸50mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.16(1H,d,J=8.4Hz),7.21-7.27(3H,m),7.32-7.43(4H,m),7.72(2H,d,J=8.2Hz),7.84(2H,d,J=8.2Hz),7.91(1H,d,J=8.4Hz),9.61(1H,s),12.99-13.16(1H,broad).Example 144

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate 0.15 g of N, N-dimethylacetamide in 3.0 mL solution at room temperature, 0.14 mL of 1-bromo-4- (trifluoromethyl) benzene, Cesium carbonate (0.31 g) and palladium acetate (11 mg) were added, and the mixture was stirred at 120 ° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (4-trifluoromethylphenyl) vinyl) benzoate was obtained.
The obtained tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (4-trifluoromethylphenyl) vinyl) benzoate solution in 15 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. did. The solvent was distilled off under reduced pressure to obtain 50 mg of 2- (4-fluoroanilino) -4-((E) -2- (4-trifluoromethylphenyl) vinyl) benzoic acid as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.16 (1H, d, J = 8.4 Hz), 7.21-7.27 (3H, m), 7.32-7.43 (4H, m), 7.72 (2H, d, J = 8.2Hz), 7.84 (2H, d, J = 8.2Hz), 7.91 (1H, d, J = 8.4Hz), 9.61 (1H, s), 12.99-13.16 (1H, broad).

実施例１４４と同様にして、以下の化合物を得た。
４−（（Ｅ）−２−（ベンゾフラン−５−イル）ビニル）−２−（４−フルオロアニリノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：6.95(1H,d,J=2.2Hz),7.12(1H,d,J=8.0Hz),7.16-7.27(4H,m),7.31-7.39(3H,m),7.57-7.64(2H,m),7.88-7.90(2H,m),8.00(1H,d,J=2.2Hz),9.60(1H,s),12.92-13.06(1H,broad).Example 145

In the same manner as in Example 144, the following compound was obtained.
4-((E) -2- (benzofuran-5-yl) vinyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.95 (1H, d, J = 2.2 Hz), 7.12 (1H, d, J = 8.0 Hz), 7.16-7.27 (4H, m), 7.31-7.39 ( 3H, m), 7.57-7.64 (2H, m), 7.88-7.90 (2H, m), 8.00 (1H, d, J = 2.2Hz), 9.60 (1H, s), 12.92-13.06 (1H, broad) .

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で３−ブロモピリジン70μL、トリブチルアミン0.23mLおよび酢酸パラジウム11mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム11mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８，溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（ピリジン−３−イル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（ピリジン−３−イル）ビニル）ベンゾアートのトリフルオロ酢酸15mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.0に調整した。有機層を分取し、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡黄色固体の２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（ピリジン−３−イル）ビニル）安息香酸46mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.13(1H,dd,J=8.2,1.2Hz),7.20-7.41(8H,m),7.91(1H,d,J=8.2Hz),8.06(1H,dt,J=8.0,1.9Hz),8.46(1H,dd,J=4.8,1.3Hz),8.77(1H,d,J=2.2Hz),9.61(1H,s),12.95-13.14(1H,broad).Example 146

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate 0.15 g of a N, N-dimethylacetamide solution (3.0 mL) was mixed with 70 μL of 3-bromopyridine, 0.23 mL of tributylamine and 11 mg of palladium acetate at room temperature. In addition, the mixture was stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, 11 mg of palladium acetate was added, and the mixture was stirred at 110 ° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (Pyridin-3-yl) vinyl) benzoate was obtained.
The obtained tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (pyridin-3-yl) vinyl) benzoate solution in 15 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. . The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 6.0 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 2- (4-fluoroanilino) -4-((E) -2- (pyridine-3) was obtained as a pale yellow solid. 46 mg of yl) vinyl) benzoic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.13 (1H, dd, J = 8.2,1.2 Hz), 7.20-7.41 (8H, m), 7.91 (1H, d, J = 8.2 Hz), 8.06 ( 1H, dt, J = 8.0,1.9Hz), 8.46 (1H, dd, J = 4.8,1.3Hz), 8.77 (1H, d, J = 2.2Hz), 9.61 (1H, s), 12.95-13.14 (1H , broad).

２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−（トリフルオロメチル）フェニル）ビニル）安息香酸15mgのメタノール4.0mLおよび酢酸エチル4.0mLの混液に、室温で5％パラジウム−炭素8.0mgを加え、水素雰囲気下、室温で10時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、白色固体の２−（４−フルオロアニリノ）−４−（２−（４−（トリフルオロメチル）フェニル）エチル）安息香酸14mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.82(2H,t,J=7.2Hz),2.94(2H,t,J=7.2Hz),6.61(1H,dd,J=8.0,1.2Hz),6.80(1H,d,J=1.2Hz),7.00-7.12(4H,m),7.40(2H,d,J=8.1Hz),7.63(2H,d,J=8.1Hz),7.81(1H,d,J=7.9Hz).Example 147

2- (4-Fluoroanilino) -4-((E) -2- (4- (trifluoromethyl) phenyl) vinyl) benzoic acid 15 mg in a mixture of methanol 4.0 mL and ethyl acetate 4.0 mL % Palladium-carbon (8.0 mg) was added, and the mixture was stirred at room temperature for 10 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to give 14 mg of 2- (4-fluoroanilino) -4- (2- (4- (trifluoromethyl) phenyl) ethyl) benzoic acid as a white solid. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.82 (2H, t, J = 7.2Hz), 2.94 (2H, t, J = 7.2Hz), 6.61 (1H, dd, J = 8.0, 1.2Hz) , 6.80 (1H, d, J = 1.2Hz), 7.00-7.12 (4H, m), 7.40 (2H, d, J = 8.1Hz), 7.63 (2H, d, J = 8.1Hz), 7.81 (1H, d, J = 7.9Hz).

Examples 148-168
In the same manner as in Example 147, the compounds shown in Table 26 were obtained.

2- (4-Fluoroanilino) -4- (2- (thiophen-3-yl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.74.2.88 (4H, m), 6.50 (1H, dd, J = 7.8,1.2Hz), 6.87 (1H, d, J = 1.2Hz), 6.96 7.10 (5H, m), 7.13 (1H, d, J = 2.2Hz), 7.45 (1H, dd, J = 4.9,3.0Hz), 7.79 (1H, d, J = 7.8Hz), 12.08 (1H, s ).

2- (4-Fluoroanilino) -4- (2- (1H-indol-4-yl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.84.2.91 (2H, m), 3.04-3.11 (2H, m), 6.43 (1H, s), 6.64 (1H, d, J = 8.0 Hz), 6.70-6.76 (2H, m), 6.85-7.06 (5H, m), 7.26 (1H, d, J = 8.0Hz), 7.29 (1H, t, J = 2.7Hz), 7.81 (1H, d, J = 8.0Hz), 11.07 (1H, s).

4- (2- (Benzothiophen-5-yl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.83 (2H, t, J = 7.2Hz), 2.97 (2H, t, J = 7.2Hz), 6.58 (1H, dd, J = 7.9, 1.2Hz) , 6.75 (1H, d, J = 1.2Hz), 6.82-6.91 (3H, m), 6.97-7.08 (1H, m), 7.19 (1H, dd, J = 8.3,1.3Hz), 7.38 (1H, d , J = 5.5Hz), 7.66 (1H, s), 7.72 (1H, d, J = 5.5Hz), 7.81 (1H, d, J = 7.9Hz), 7.90 (1H, d, J = 8.3Hz).

4- (2- (Benzofuran-5-yl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.82 (2H, m), 2.91-2.97 (2H, m), 6.51-6.56 (1H, m), 6.74 (1H, s), 6.80-6.91 (5H, m), 7.12 (1H, dd, J = 8.3,1.7Hz), 7.41 (1H, d, J = 1.5Hz), 7.49 (1H, d, J = 8.3Hz), 7.79 (1H, d, J = 7.8Hz), 7.95 (1H, d, J = 2.2Hz).

2- (4-Fluoroanilino) -4- (2- (4-hydroxyphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.66-2.76 (4H, m), 6.50 (1H, dd, J = 8.0, 1.4 Hz), 6.66 (2H, d, J = 8.3 Hz), 6.74 ( 1H, d, J = 1.4Hz), 6.88-6.95 (4H, m), 7.00-7.07 (2H, m), 7.79 (1H, d, J = 8.0Hz), 7.95 (1H, s), 9.19 (1H , s).

4- (2-cyclohexylethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 0.80-0.93 (2H, m), 1.05-1.25 (4H, m), 1.35-1.43 (2H, m), 1.55-1.73 (5H, m), 2.45 -2.50 (2H, m), 6.57 (1H, dd, J = 8.1,1.3Hz), 6.88 (1H, d, J = 1.3Hz), 7.14-7.26 (4H, m), 7.79 (1H, d, J = 8.1Hz).

4- (3-cyclohexylpropyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 0.75-0.87 (2H, m), 1.05-1.24 (6H, m), 1.46-1.67 (7H, m), 2.42-2.48 (2H, m), 6.60 (1H, dd, J = 8.1,1.2Hz), 6.87 (1H, d, J = 1.2Hz), 7.16-7.22 (2H, m), 7.24-7.29 (2H, m), 7.79 (1H, d, J = 8.1Hz), 9.42-9.72 (1H, broad).

2- (4-Fluoroanilino) -4- (2- (3-hydroxyphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.73-2.77 (4H, m), 6.53-6.62 (3H, m), 6.64 (1H, dd, J = 8.1, 1.4 Hz), 6.78 (1H, d , J = 1.4Hz), 7.01-7.15 (5H, m), 7.80 (1H, d, J = 8.1Hz), 9.04-9.43 (1H, broad).

2- (4-Fluoroanilino) -4- (2- (2-methylphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.18 (3H, s), 2.71-2.85 (4H, m), 6.67 (1H, dd, J = 8.1, 1.4 Hz), 6.78 (1H, d, J = 1.4Hz), 7.04-7.15 (8H, m), 7.81 (1H, d, J = 8.1Hz).

2- (4-Fluoroanilino) -4- (2- (4-fluorophenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.74-2.86 (4H, m), 6.64 (1H, dd, J = 8.1,0.9Hz), 6.78 (1H, d, J = 0.9Hz), 7.04- 7.22 (8H, m), 7.80 (1H, d, J = 8.1Hz).

2- (4-Fluoroanilino) -4- (2- (3-fluoro-4-methylphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.19 (3H, s), 2.77-2.83 (4H, m), 6.64 (1H, dd, J = 8.2, 1.5 Hz), 6.81 (1H, d, J = 1.5Hz), 6.88 (1H, dd, J = 7.8,1.2Hz), 6.96 (1H, dd, J = 11.2,1.2Hz), 7.08-7.18 (5H, m), 7.80 (1H, d, J = 8.2Hz).

4- (2- (2,4-Difluorophenyl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.72-2.87 (4H, m), 6.61 (1H, dd, J = 8.1, 1.2 Hz), 6.75 (1H, d, J = 1.2 Hz), 6.99 ( 1H, td, J = 8.5,2.7Hz), 7.05-7.29 (6H, m), 7.80 (1H, d, J = 8.1Hz).

2- (4-Fluoroanilino) -4- (2- (4-methoxyphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.73-2.79 (4H, m), 3.71 (3H, s), 6.63 (1H, dd, J = 8.0, 1.1 Hz), 6.76 (1H, s), 6.83 (2H, d, J = 8.5Hz), 7.02-7.14 (6H, m), 7.80 (1H, d, J = 8.0Hz).

2- (4-Fluoroanilino) -4- (2- (2-hydroxyphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.70-2.79 (4H, m), 6.59 (1H, dd, J = 8.1,1.5 Hz), 6.67 (1H, td, J = 7.4,1.1 Hz), 6.78-6.83 (2H, m), 6.93 (1H, dd, J = 7.4,1.6Hz), 6.99-7.13 (5H, m), 7.80 (1H, d, J = 8.1Hz), 9.29 (1H, s) .

4- (2- (Benzothiophen-3-yl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.93 (2H, t, J = 7.4 Hz), 3.09 (2H, t, J = 7.4 Hz), 6.70 (1H, d, J = 8.3 Hz), 6.82 (1H, s), 6.99-7.08 (4H, m), 7.34-7.41 (3H, m), 7.76-7.85 (2H, m), 7.97-8.02 (1H, m).

4- (2- (Benzo-1,3-dioxol-5-yl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.72-2.77 (4H, m), 5.95 (2H, s), 6.59-6.65 (2H, m), 6.76-6.83 (3H, m), 7.10-7.15 (4H, m), 7.80 (1H, d, J = 8.0Hz).

4- (2- (3-Aminophenyl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.62-2.76 (4H, m), 6.28 (1H, d, J = 7.7Hz), 6.37 (1H, s), 6.41 (1H, dd, J = 7.7 1.3Hz), 6.63 (1H, dd, J = 8.2, 1.4Hz), 6.79 (1H, d, J = 1.4Hz), 6.90 (1H, t, J = 7.7Hz), 7.04-7.16 (4H, m ), 7.80 (1H, d, J = 8.2Hz).

4- (2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.67-2.78 (4H, m), 4.18 (4H, s), 6.60-6.66 (3H, m), 6.74 (1H, d, J = 8.0 Hz), 6.81 (1H, s), 7.07-7.16 (4H, m), 7.79 (1H, d, J = 8.0Hz).

2- (4-Fluoroanilino) -4- (2- (3-methoxyphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.77-2.83 (4H, m), 3.70 (3H, s), 6.65 (1H, dd, J = 8.1, 1.5 Hz), 6.71-6.78 (3H, m ), 6.81 (1H, d, J = 1.5Hz), 7.04-7.20 (5H, m), 7.80 (1H, d, J = 8.1Hz).

4- (2- (4-Ethylphenyl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.15 (3H, t, J = 7.6 Hz), 2.56 (2H, q, J = 7.6 Hz), 2.76-2.81 (4H, m), 6.64 (1H, dd, J = 8.0,1.5Hz), 6.82 (1H, d, J = 1.5Hz), 7.05-7.15 (8H, m), 7.80 (1H, d, J = 8.0Hz).

2- (4-Fluoroanilino) -4- (2- (4- (1H-pyrazol-1-yl) phenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.79 (2H, t, J = 7.4 Hz), 2.88 (2H, t, J = 7.4 Hz), 6.50-6.55 (2H, m), 6.77 (1H, s), 6.86-6.96 (4H, m), 7.27 (2H, d, J = 8.5Hz), 7.72 (1H, d, J = 2.4Hz), 7.74 (2H, d, J = 8.5Hz), 7.81 ( 1H, d, J = 7.8Hz), 8.46 (1H, d, J = 2.4Hz), 11.89-12.02 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、室温で２−ブロモベンゾトリフルオリド0.11mL、炭酸セシウム0.22g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.0mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.5mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.0mgを加え、110℃で20時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−フェネチル−２−（２−（トリフルオロメチル）アニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−フェネチル−２−（２−（トリフルオロメチル）アニリノ）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の４−フェネチル−２−（２−（トリフルオロメチル）アニリノ）安息香酸17mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.84(4H,s),6.79(1H,d,J=8.3Hz),6.86-6.90(1H,m),7.13-7.32(7H,m),7.55(1H,t,J=7.7Hz),7.71(1H,d,J=7.8Hz),7.85(1H,d,J=8.3Hz),9.95(1H,s),13.13(1H,s).Example 169

To a solution of tert-butyl 2-amino-4-phenethylbenzoate (0.10 g) in toluene (3.0 mL) at room temperature is 2-bromobenzotrifluoride (0.11 mL), cesium carbonate (0.22 g), tris (dibenzylideneacetone) dipalladium (0) 3.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (8.0 mg) were added, and the mixture was stirred at 110 ° C. for 24 hours. After cooling the reaction mixture to room temperature, 1.5 mg of palladium acetate, 3.0 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.0 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. And stirred at 110 ° C. for 20 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 4-phenethyl-2- (2- (tri Fluoromethyl) anilino) benzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 4-phenethyl-2- (2- (trifluoromethyl) anilino) benzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 17 mg of white solid 4-phenethyl-2- (2- (trifluoromethyl) anilino) benzoic acid was added. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.84 (4H, s), 6.79 (1H, d, J = 8.3 Hz), 6.86-6.90 (1H, m), 7.13-7.32 (7H, m), 7.55 (1H, t, J = 7.7Hz), 7.71 (1H, d, J = 7.8Hz), 7.85 (1H, d, J = 8.3Hz), 9.95 (1H, s), 13.13 (1H, s).

Examples 170-175
In the same manner as in Example 169, the compounds shown in Table 27 were obtained.

4-phenethyl-2- (4- (trifluoromethyl) anilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.89 (4H, s), 6.85 (1H, dd, J = 8.1, 1.2 Hz), 7.13-7.31 (8H, m), 7.57 (2H, d, J = 8.5Hz), 7.86 (1H, d, J = 8.3Hz), 9.72 (1H, s), 13.11 (1H, s).

2- (2,5-Difluoroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.88 (4H, s), 6.79-6.90 (2H, m), 7.03-7.07 (1H, m), 7.12-7.37 (7H, m), 7.85 (1H , d, J = 8.0 Hz), 9.78 (1H, s), 13.17 (1H, s).

2- (2,4-Dimethylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.10 (3H, s), 2.27 (3H, s), 2.72-2.84 (4H, m), 6.52-6.55 (1H, m), 6.60 (1H, dd , J = 8.2,1.3Hz), 6.95-7.01 (2H, m), 7.08-7.27 (6H, m), 7.78 (1H, d, J = 8.3Hz), 9.36 (1H, s), 12.80 (1H, s).

2- (2,3-Dimethylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.05 (3H, s), 2.27 (3H, s), 2.71-2.83 (4H, m), 6.49 (1H, dd, J = 6.2, 1.3 Hz), 6.60 (1H, dd, J = 8.3,1.5Hz), 6.93 (1H, d, J = 7.8Hz), 6.99 (1H, d, J = 7.3Hz), 7.06 (1H, t, J = 7.7Hz), 7.11-7.20 (3H, m), 7.21-7.27 (2H, m), 7.79 (1H, d, J = 8.0Hz), 9.43 (1H, s), 12.83 (1H, s).

2- (3-Fluoroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.86 (4H, s), 6.74-6.89 (3H, m), 6.95 (1H, dt, J = 11.2, 2.2 Hz), 7.05 (1H, d, J = 1.4Hz), 7.15-7.22 (3H, m), 7.23-7.34 (3H, m), 7.83 (1H, d, J = 8.0Hz), 9.63 (1H, s), 13.03 (1H, s).

2- (3,4-Difluoroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.84 (4H, s), 6.74 (1H, d, J = 8.3 Hz), 6.84-6.95 (2H, m), 7.15-7.38 (7H, m), 7.82 (1H, d, J = 8.0Hz), 9.53 (1H, s), 13.00 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、室温で３−ブロモトルエン0.10mL、炭酸セシウム0.22g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.0mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.5mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.0mgを加え、110℃で20時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（３−メチルアニリノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（３−メチルアニリノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；77-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（３−メチルアニリノ）−４−フェネチル安息香酸15mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.28(3H,s),2.77-2.88(4H,m),6.67(1H,dd,J=8.3,1.5Hz),6.83-6.89(2H,m),6.93-7.00(2H,m),7.14-7.22(4H,m),7.23-7.29(2H,m),7.81(1H,d,J=8.0Hz),9.58(1H,s),12.91(1H,s).Example 176

To a solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g in toluene 3.0 mL, at room temperature, 0.10 mL 3-bromotoluene, 0.22 g cesium carbonate, 3.0 mg tris (dibenzylideneacetone) dipalladium (0) and 8.0 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl was added and stirred at 110 ° C. for 24 hours. After cooling the reaction mixture to room temperature, 1.5 mg of palladium acetate, 3.0 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.0 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. And stirred at 110 ° C. for 20 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (3-methylanilino) -4-phenethyl. I got benzoart.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2- (3-methylanilino) -4-phenethylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 77-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (3- 15 mg of methylanilino) -4-phenethylbenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.28 (3H, s), 2.77-2.88 (4H, m), 6.67 (1H, dd, J = 8.3, 1.5 Hz), 6.83-6.89 (2H, m ), 6.93-7.00 (2H, m), 7.14-7.22 (4H, m), 7.23-7.29 (2H, m), 7.81 (1H, d, J = 8.0Hz), 9.58 (1H, s), 12.91 ( 1H, s).

Examples 177-181
In the same manner as in Example 176, the compounds shown in Table 28 were obtained.

2- (4-Methylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.28 (3H, s), 2.75-2.89 (4H, m), 6.64 (1H, d, J = 7.8 Hz), 6.85 (1H, s), 6.95 ( 2H, d, J = 8.0Hz), 7.08-7.32 (7H, m), 7.79 (1H, d, J = 8.3Hz), 9.52 (1H, s), 12.86 (1H, s).

2- (3,4-Dimethylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.19 (6H, s), 2.72-2.88 (4H, m), 6.60-6.66 (1H, m), 6.80 (1H, dd, J = 8.0, 2.2 Hz ), 6.86-6.95 (2H, m), 7.07 (1H, d, J = 8.1Hz), 7.12-7.30 (5H, m), 7.78 (1H, d, J = 8.0Hz), 9.50 (1H, s) , 12.84 (1H, s).

2- (2-Ethylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.12 (3H, t, J = 7.6 Hz), 2.54 (2H, q, J = 7.6 Hz), 2.73-2.85 (4H, m), 6.60-6.70 ( 2H, m), 7.04-7.31 (9H, m), 7.80 (1H, d, J = 8.0Hz), 9.54 (1H, s), 12.88 (1H, s).

2- (4-Chloroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.82-2.87 (4H, m), 6.73 (1H, dd, J = 8.2,1.6Hz), 6.93 (1H, d, J = 1.2Hz), 7.03- 7.09 (2H, m), 7.15-7.34 (7H, m), 7.82 (1H, d, J = 8.3Hz), 9.50-9.70 (1H, broad), 12.80-13.20 (1H, broad).

2- (2-methoxyanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.89 (4H, m), 3.81 (3H, s), 6.67 (1H, dd, J = 8.2, 1.3 Hz), 6.87 (1H, td, J = 7.6,1.6Hz), 6.94-7.12 (4H, m), 7.15-7.30 (5H, m), 7.80 (1H, d, J = 8.0Hz), 9.56 (1H, s), 12.70-13.00 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、室温で１，３−ジクロロ−２−ヨードベンゼン0.23g、炭酸セシウム0.22g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.0mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.5mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.0mgを加え、110℃で20時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（２，６−ジクロロアニリノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（２，６−ジクロロアニリノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；75-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（２，６−ジクロロアニリノ）−４−フェネチル安息香酸9.4mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.76(4H,m),6.04(1H,d,J=1.2Hz),6.66(1H,dd,J=8.1,1.2Hz),7.08-7.24(5H,m),7.36(1H,t,J=8.2Hz),7.61(2H,d,J=8.3Hz),7.80(1H,d,J=8.0Hz),9.52(1H,s),13.00(1H,s).Example 182

tert-Butyl-2-amino-4-phenethylbenzoate 0.10 g of toluene 3.0 mL solution at room temperature, 1,3-dichloro-2-iodobenzene 0.23 g, cesium carbonate 0.22 g, tris (dibenzylideneacetone) dipalladium (0) 3.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 8.0 mg were added and stirred at 110 ° C. for 24 hours. After cooling the reaction mixture to room temperature, 1.5 mg of palladium acetate, 3.0 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.0 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. And stirred at 110 ° C. for 20 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2 (2,6-dichloroanilino). -4-Phenethylbenzoate was obtained.
10 mL of trifluoroacetic acid was added to the resulting tert-butyl = 2- (2,6-dichloroanilino) -4-phenethylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 75-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give a white solid 2- (2, 9.4 mg of 6-dichloroanilino) -4-phenethylbenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.76 (4H, m), 6.04 (1H, d, J = 1.2 Hz), 6.66 (1H, dd, J = 8.1, 1.2 Hz), 7.08-7.24 ( 5H, m), 7.36 (1H, t, J = 8.2Hz), 7.61 (2H, d, J = 8.3Hz), 7.80 (1H, d, J = 8.0Hz), 9.52 (1H, s), 13.00 ( 1H, s).

実施例１８２と同様にして、以下の化合物を得た。
２−（４−フルオロ−３−メチルアニリノ）−４−フェネチル安息香酸
¹H-NMR(DMSO-d₆)δ値：2.21(1H,d,J=1.7Hz),2.76-2.87(4H,m),6.65(1H,dd,J=8.3,1.5Hz),6.82(1H,s),6.87-6.93(1H,m),7.03-7.11(2H,m),7.13-7.22(3H,m),7.23-7.29(2H,m),7.79(1H,d,J=8.0Hz),9.48(1H,s),12.75-13.05(1H,broad).Example 183

In the same manner as in Example 182, the following compound was obtained.
2- (4-Fluoro-3-methylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.21 (1H, d, J = 1.7 Hz), 2.76-2.87 (4H, m), 6.65 (1H, dd, J = 8.3, 1.5 Hz), 6.82 ( 1H, s), 6.87-6.93 (1H, m), 7.03-7.11 (2H, m), 7.13-7.22 (3H, m), 7.23-7.29 (2H, m), 7.79 (1H, d, J = 8.0 Hz), 9.48 (1H, s), 12.75-13.05 (1H, broad).

２−（４−アセチルアニリノ）−４−フェネチル安息香酸10mgのメタノール1.0mLおよび酢酸エチル1.0mLの混液に、室温で5％パラジウム−炭素2.0mgを加え、水素雰囲気下、40℃で7時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、減圧下で溶媒を留去させ、白色固体の２−（４−エチルアニリノ）−４−フェネチル安息香酸9.7mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.17(3H,t,J=7.6Hz),2.53(2H,q,J=7.6Hz),2.72-2.88(4H,m),6.49(1H,dd,J=7.8,1.5Hz),6.86-6.92(3H,m),7.02-7.08(2H,m),7.16-7.30(5H,m),7.80(1H,d,J=7.8Hz),11.70-11.85(1H,broad).Example 184

To a mixture of 10 mg of 2- (4-acetylanilino) -4-phenethylbenzoic acid in 1.0 mL of methanol and 1.0 mL of ethyl acetate was added 2.0 mg of 5% palladium-carbon at room temperature, and a hydrogen atmosphere at 40 ° C. for 7 hours. Stir. After cooling the reaction mixture to room temperature, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure to obtain 9.7 mg of 2- (4-ethylanilino) -4-phenethylbenzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.17 (3H, t, J = 7.6 Hz), 2.53 (2H, q, J = 7.6 Hz), 2.72-2.88 (4H, m), 6.49 (1H, dd, J = 7.8,1.5Hz), 6.86-6.92 (3H, m), 7.02-7.08 (2H, m), 7.16-7.30 (5H, m), 7.80 (1H, d, J = 7.8Hz), 11.70 -11.85 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート94mgのトルエン3.0mL溶液に、室温で４−ヨードアニソール0.20g、炭酸セシウム0.23g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で6時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、４−ヨードアニソール0.20g、炭酸セシウム0.23g、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で4時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−メトキシアニリノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−メトキシアニリノ）−４−フェニルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（４−メトキシアニリノ）−４−フェニル安息香酸44mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.77(3H,s),6.95-7.01(3H,m),7.14(1H,d,J=1.7Hz),7.24-7.30(2H,m),7.35-7.48(3H,m),7.50-7.55(2H,m),7.95(1H,d,J=8.3Hz),9.51(1H,s),13.00(1H,s).Example 185

To a 3.0 mL toluene solution of 94 mg tert-butyl = 2-amino-4-phenylbenzoate at room temperature, 0.20 g 4-iodoanisole, 0.23 g cesium carbonate, 3.2 mg tris (dibenzylideneacetone) dipalladium (0) and 2 -8.3 mg of dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl was added and stirred at 110 ° C. for 6 hours. After cooling the reaction mixture to room temperature, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. , And stirred at 110 ° C. for 12 hours. After the reaction mixture was cooled to room temperature, 0.20 g of 4-iodoanisole, 0.23 g of cesium carbonate, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino-2 ′, 4 8.3 mg of ', 6'-triisopropylbiphenyl was added and stirred at 110 ° C. for 4 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-methoxyanilino) -4. -Phenylbenzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2- (4-methoxyanilino) -4-phenylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, and the solid was collected by filtration to obtain 44 mg of 2- (4-methoxyanilino) -4-phenylbenzoic acid as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.77 (3H, s), 6.95-7.01 (3H, m), 7.14 (1H, d, J = 1.7 Hz), 7.24-7.30 (2H, m), 7.35-7.48 (3H, m), 7.50-7.55 (2H, m), 7.95 (1H, d, J = 8.3Hz), 9.51 (1H, s), 13.00 (1H, s).

Examples 186, 187
In the same manner as in Example 185, the compounds shown in Table 29 were obtained.

2- (2-methoxyanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.84 (3H, s), 6.95-7.20 (4H, m), 7.36-7.53 (5H, m), 7.56-7.63 (2H, m), 7.98 (1H , d, J = 8.3Hz), 9.65 (1H, s), 12.85-13.15 (1H, broad).

2- (3-Chloroanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.07-7.11 (1H, m), 7.16 (1H, dd, J = 8.3,1.7 Hz), 7.31-7.51 (7H, m), 7.59-7.64 (2H , m), 8.00 (1H, d, J = 8.3Hz), 9.68 (1H, s), 13.21 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート94mgのトルエン3.0mL溶液に、室温で４−ブロモトルエン0.11mL、炭酸セシウム0.23g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で6時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−メチルアニリノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−メチルアニリノ）−４−フェニルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の２−（４−メチルアニリノ）−４−フェニル安息香酸8.7mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.30(3H,s),7.02(1H,dd,J=8.3,1.7Hz),7.12-7.28(4H,m),7.31-7.34(1H,m),7.36-7.48(3H,m),7.53-7.58(2H,m),7.97(1H,d,J=8.3Hz),9.62(1H,s),13.06(1H,s).Example 188

To a 3.0 mL toluene solution of 94 mg tert-butyl-2-amino-4-phenylbenzoate at room temperature, 0.11 mL 4-bromotoluene, 0.23 g cesium carbonate, 3.2 mg tris (dibenzylideneacetone) dipalladium (0) and 2 -8.3 mg of dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl was added and stirred at 110 ° C. for 6 hours. After cooling the reaction mixture to room temperature, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. , And stirred at 110 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-methylanilino) -4-phenyl. I got benzoart.
To the obtained tert-butyl = 2- (4-methylanilino) -4-phenylbenzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 8.7 mg of 2- (4-methylanilino) -4-phenylbenzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.30 (3H, s), 7.02 (1H, dd, J = 8.3, 1.7 Hz), 7.12-7.28 (4H, m), 7.31-7.34 (1H, m ), 7.36-7.48 (3H, m), 7.53-7.58 (2H, m), 7.97 (1H, d, J = 8.3Hz), 9.62 (1H, s), 13.06 (1H, s).

Examples 189-194
In the same manner as in Example 188, the compounds shown in Table 30 were obtained.

2- (3-Methylanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.31 (3H, s), 6.92 (1H, d, J = 7.6 Hz), 7.06 (1H, dd, J = 8.3, 1.7 Hz), 7.11 (1H, s), 7.15 (1H, d, J = 8.0Hz), 7.27 (1H, t, J = 7.8Hz), 7.37-7.49 (4H, m), 7.55-7.61 (2H, m), 7.98 (1H, d , J = 8.3Hz), 9.67 (1H, s), 13.10 (1H, s).

4-Phenyl-2- (4- (trifluoromethoxy) anilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.13 (1H, dd, J = 8.3,1.7 Hz), 7.33-7.50 (8H, m), 7.60-7.65 (2H, m), 8.01 (1H, d , J = 8.3Hz), 9.74 (1H, s), 13.20 (1H, s).

4-Phenyl-2- (3- (trifluoromethoxy) anilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.01 (1H, d, J = 8.3 Hz), 7.18 (1H, dd, J = 8.3,1.5 Hz), 7.31-7.54 (7H, m), 7.60- 7.65 (2H, m), 8.02 (1H, d, J = 8.3Hz), 9.74 (1H, s), 13.24 (1H, s).

2- (4-Nitroanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.35 to 7.53 (6H, m), 7.70-7.76 (3H, m), 8.05 (1H, d, J = 8.3 Hz), 8.17 (2H, d, J = 9.0Hz), 9.92 (1H, s), 13.37 (1H, s).

2- (4-Methoxy-2-methylanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.18 (3H, s), 3.76 (3H, s), 6.71-6.75 (1H, m), 6.84 (1H, dd, J = 8.5, 2.9 Hz), 6.91-6.96 (2H, m), 7.25 (1H, d, J = 8.5Hz), 7.34-7.50 (5H, m), 7.94 (1H, d, J = 8.3Hz), 9.34 (1H, s), 12.95 (1H, s).

4-Phenyl-2- (2- (trifluoromethoxy) anilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.14-7.22 (2H, m), 7.38-7.51 (6H, m), 7.61-7.66 (2H, m), 7.78 (1H, dd, J = 8.0, 1.5Hz), 8.03 (1H, d, J = 8.3Hz), 10.07 (1H, s), 13.33 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、室温で１−ブロモ−４−（トリフルオロメトキシ）ベンゼン0.13mL、炭酸セシウム0.23g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で6時間攪拌した。反応混合物を室温まで冷却した後、室温で酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝４−フェネチル−２−（４−（トリフルオロメトキシ）アニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−フェネチル−２−（４−（トリフルオロメトキシ）アニリノ）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の４−フェネチル−２−（４−（トリフルオロメトキシ）アニリノ）安息香酸20mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.85(4H,s),6.72-6.78(1H,m),6.97(1H,s),7.11-7.30(9H,m),7.83(1H,d,J=8.0Hz),9.62(1H,s),13.00(1H,s).Example 195

To a solution of tert-butyl 2-amino-4-phenethylbenzoate 0.10 g in toluene 3.0 mL at room temperature, 0.13 mL of 1-bromo-4- (trifluoromethoxy) benzene, 0.23 g of cesium carbonate, tris (dibenzylideneacetone) 3.2 mg of dipalladium (0) and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added and stirred at 110 ° C. for 6 hours. After cooling the reaction mixture to room temperature, 1.6 mg palladium acetate, 3.2 mg tris (dibenzylideneacetone) dipalladium (0) and 8.3 mg 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl at room temperature. And stirred at 110 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl 4-phenethyl-2- (4- (tri Fluoromethoxy) anilino) benzoate was obtained.
To the obtained tert-butyl = 4-phenethyl-2- (4- (trifluoromethoxy) anilino) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, the solid was collected by filtration, and 20 mg of white solid 4-phenethyl-2- (4- (trifluoromethoxy) anilino) benzoic acid was added. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.85 (4H, s), 6.72-6.78 (1H, m), 6.97 (1H, s), 7.11-7.30 (9H, m), 7.83 (1H, d , J = 8.0Hz), 9.62 (1H, s), 13.00 (1H, s).

Examples 196-199
In the same manner as in Example 195, the compounds shown in Table 31 were obtained.

2- (4-Nitroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.92 (4H, s), 7.00 (1H, dd, J = 8.1, 1.5 Hz), 7.06-7.12 (2H, m), 7.18-7.32 (6H, m ), 7.88 (1H, d, J = 8.0Hz), 8.05-8.11 (2H, m), 9.82 (1H, s), 13.10-13.35 (1H, broad).

4-phenethyl-2- (3- (trifluoromethoxy) anilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.86 (4H, s), 6.79 (1H, dd, J = 8.2, 1.3 Hz), 6.93-6.98 (1H, m), 7.03-7.09 (2H, m ), 7.12 (1H, s), 7.15-7.21 (3H, m), 7.23-7.30 (2H, m), 7.38 (1H, t, J = 8.2Hz), 7.84 (1H, d, J = 8.1Hz) , 9.62 (1H, s), 13.05 (1H, s).

2- (4-Methoxy-2-methylanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.09 (3H, s), 2.69-2.81 (4H, m), 3.76 (3H, s), 6.33 (1H, d, J = 1.2 Hz), 6.55 ( 1H, dd, J = 8.3,1.5Hz), 6.77 (1H, dd, J = 8.5,2.9Hz), 6.89 (1H, d, J = 3.0Hz), 7.00 (1H, d, J = 8.6Hz), 7.09-7.27 (5H, m), 7.76 (1H, d, J = 8.0Hz), 9.22 (1H, s), 12.74 (1H, s).

4-phenethyl-2- (2- (trifluoromethoxy) anilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.87 (4H, m), 6.76-6.81 (1H, m), 6.98-7.02 (1H, m), 7.08-7.15 (1H, m), 7.15-7.23 (3H, m), 7.24-7.34 (4H, m), 7.40-7.44 (1H, m), 7.85 (1H, d, J = 8.3Hz), 9.98 (1H, s), 13.14 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、室温で１−クロロ−３−ヨードベンゼン0.11mL、炭酸セシウム0.23g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で6時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（３−クロロアニリノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（３−クロロアニリノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の２−（３−クロロアニリノ）−４−フェネチル安息香酸21mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.86(4H,s),6.76(1H,dd,J=8.2,1.3Hz),6.97-7.06(3H,m),7.15-7.21(4H,m),7.24-7.32(3H,m),7.83(1H,d,J=8.1Hz),9.58(1H,s),13.02(1H,s).Example 200

To a solution of tert-butyl 2-amino-4-phenethylbenzoate (0.10 g) in toluene (3.0 mL) at room temperature is 1-chloro-3-iodobenzene (0.11 mL), cesium carbonate (0.23 g), tris (dibenzylideneacetone) dipalladium (0 ) 3.2 mg and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added and stirred at 110 ° C. for 6 hours. After cooling the reaction mixture to room temperature, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. , And stirred at 110 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (3-chloroanilino) -4-phenethyl. I got benzoart.
To the resulting tert-butyl = 2- (3-chloroanilino) -4-phenethylbenzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 21 mg of 2- (3-chloroanilino) -4-phenethylbenzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.86 (4H, s), 6.76 (1H, dd, J = 8.2, 1.3 Hz), 6.97-7.06 (3H, m), 7.15-7.21 (4H, m ), 7.24-7.32 (3H, m), 7.83 (1H, d, J = 8.1Hz), 9.58 (1H, s), 13.02 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.10gのトルエン3.0mL溶液に、室温で４−（４−ブロモフェニル）モルホリン0.21g、炭酸セシウム0.23g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で6時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、４−（４−ブロモフェニル）モルホリン0.21g、炭酸セシウム0.23g、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で4時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−モルホリノアニリノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−モルホリノアニリノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；45-80％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（４−モルホリノアニリノ）−４−フェネチル安息香酸11mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.72-2.85(4H,m),3.09(4H,t,J=4.8Hz),3.75(4H,t,J=4.8Hz),6.58(1H,d,J=8.3Hz),6.72(1H,s),6.92(2H,d,J=9.0Hz),6.97(2H,d,J=9.0Hz),7.12-7.22(3H,m),7.22-7.30(2H,m),7.76(1H,d,J=8.0Hz),9.40(1H,s),12.76(1H,s).Example 201

To a 3.0 mL toluene solution of 0.10 g of tert-butyl-2-amino-4-phenethylbenzoate at room temperature, 0.21 g of 4- (4-bromophenyl) morpholine, 0.23 g of cesium carbonate, tris (dibenzylideneacetone) dipalladium ( 0) 3.2 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (8.3 mg) were added, and the mixture was stirred at 110 ° C. for 6 hours. After cooling the reaction mixture to room temperature, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. , And stirred at 110 ° C. for 12 hours. After the reaction mixture was cooled to room temperature, 0.21 g of 4- (4-bromophenyl) morpholine, 0.23 g of cesium carbonate, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino -2 ′, 4 ′, 6′-triisopropylbiphenyl (8.3 mg) was added, and the mixture was stirred at 110 ° C. for 4 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-morpholinoanilino) -4. -Phenethylbenzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2- (4-morpholinoanilino) -4-phenethylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 45-80% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4- 11 mg of morpholinoanilino) -4-phenethylbenzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.72-2.85 (4H, m), 3.09 (4H, t, J = 4.8 Hz), 3.75 (4H, t, J = 4.8 Hz), 6.58 (1H, d, J = 8.3Hz), 6.72 (1H, s), 6.92 (2H, d, J = 9.0Hz), 6.97 (2H, d, J = 9.0Hz), 7.12-7.22 (3H, m), 7.22- 7.30 (2H, m), 7.76 (1H, d, J = 8.0Hz), 9.40 (1H, s), 12.76 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート94mgのトルエン3.0mL溶液に、室温で４−（４−ブロモフェニル）モルホリン0.21g、炭酸セシウム0.23g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で6時間攪拌した。反応混合物を室温まで冷却した後、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、４−（４−ブロモフェニル）モルホリン0.21g、炭酸セシウム0.23g、酢酸パラジウム1.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.2mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル8.3mgを加え、110℃で4時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−モルホリノアニリノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−モルホリノアニリノ）−４−フェニルベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-80％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の２−（４−モルホリノアニリノ）−４−フェニル安息香酸31mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.10(4H,t,J=4.8Hz),3.74(4H,t,J=4.8Hz),6.93-6.99(1H,m),6.99(2H,d,J=8.8Hz),7.15-7.19(1H,m),7.21(2H,d,J=8.8Hz),7.35-7.47(3H,m),7.50-7.55(2H,m),7.94(1H,d,J=8.3Hz),9.50(1H,s),12.96(1H,s).Example 202

To a 3.0 mL toluene solution of 94 mg of tert-butyl-2-amino-4-phenylbenzoate at room temperature, 0.21 g of 4- (4-bromophenyl) morpholine, 0.23 g of cesium carbonate, tris (dibenzylideneacetone) dipalladium (0 ) 3.2 mg and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added and stirred at 110 ° C. for 6 hours. After cooling the reaction mixture to room temperature, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 8.3 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. , And stirred at 110 ° C. for 12 hours. After the reaction mixture was cooled to room temperature, 0.21 g of 4- (4-bromophenyl) morpholine, 0.23 g of cesium carbonate, 1.6 mg of palladium acetate, 3.2 mg of tris (dibenzylideneacetone) dipalladium (0) and 2-dicyclohexylphosphino -2 ′, 4 ′, 6′-triisopropylbiphenyl (8.3 mg) was added, and the mixture was stirred at 110 ° C. for 4 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-morpholinoanilino) -4. -Phenylbenzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2- (4-morpholinoanilino) -4-phenylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 50-80% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4- Morpholinoanilino) -4-phenylbenzoic acid 31 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.10 (4H, t, J = 4.8 Hz), 3.74 (4H, t, J = 4.8 Hz), 6.93-6.99 (1H, m), 6.99 (2H, d, J = 8.8Hz), 7.15-7.19 (1H, m), 7.21 (2H, d, J = 8.8Hz), 7.35-7.47 (3H, m), 7.50-7.55 (2H, m), 7.94 (1H , d, J = 8.3Hz), 9.50 (1H, s), 12.96 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのトルエン2.1mL溶液に、室温でエタノール0.6mL、水0.3mL、３−フルオロフェニルボロン酸46mg、炭酸水素ナトリウム69mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）16mgを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、テトラキス（トリフェニルホスフィン）パラジウム（０）16mgを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、トルエンおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（３−フルオロフェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（３−フルオロフェニル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にヘキサンを加え、固形物をろ取し、黄色固体の２−（４−フルオロアニリノ）−４−（３−フルオロフェニル）安息香酸56mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.07(1H,dd,J=8.3,1.7Hz),7.19-7.29(4H,m),7.35-7.45(4H,m),7.49(1H,td,J=8.1,6.2Hz),7.98(1H,d,J=8.3Hz),9.63(1H,s),13.12-13.21(1H,broad).Example 203

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.10 g in toluene 2.1 mL solution at room temperature 0.6 mL ethanol, water 0.3 mL, 3-fluorophenylboronic acid 46 mg, sodium bicarbonate 69 mg Then, 16 mg of tetrakis (triphenylphosphine) palladium (0) was added, and the mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 16 mg of tetrakis (triphenylphosphine) palladium (0) was added, and the mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, toluene and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(3-Fluorophenyl) benzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2- (4-fluoroanilino) -4- (3-fluorophenyl) benzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, hexane was added to the resulting residue, the solid was collected by filtration, and 56 mg of 2- (4-fluoroanilino) -4- (3-fluorophenyl) benzoic acid as a yellow solid. Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.07 (1H, dd, J = 8.3,1.7 Hz), 7.19-7.29 (4H, m), 7.35-7.45 (4H, m), 7.49 (1H, td , J = 8.1, 6.2Hz), 7.98 (1H, d, J = 8.3Hz), 9.63 (1H, s), 13.12-13.21 (1H, broad).

Examples 204-223
In the same manner as in Example 203, the compounds shown in Table 32 were obtained.

2- (4-Fluoroanilino) -4- (2-fluorophenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.95 (1H, d, J = 8.3 Hz), 7.17-7.38 (7H, m), 7.40-7.47 (1H, m), 7.50 (1H, td, J = 7.9,1.5Hz), 7.99 (1H, d, J = 8.3Hz), 9.60 (1H, s), 13.18 (1H, s).

2- (4-Fluoroanilino) -4- (3-fluoro-4-methylphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.25 (3H, s), 7.05 (1H, dd, J = 8.3, 1.7 Hz), 7.18-7.27 (3H, m), 7.29-7.40 (5H, m ), 7.96 (1H, d, J = 8.3Hz), 9.58-9.70 (1H, broad).

2- (4-Fluoroanilino) -4- (4-fluoro-2-methylphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.21 (3H, s), 6.72 (1H, dd, J = 8.3, 1.5 Hz), 6.80-6.90 (1H, m), 7.05 (1H, td, J = 8.6,2.6Hz), 7.14 (1H, dd, J = 10.2,2.4Hz), 7.16-7.24 (3H, m), 7.28-7.35 (2H, m), 7.94 (1H, d, J = 8.0Hz) , 9.59 (1H, s), 13.00-13.20 (1H, broad).

4- (4-Chlorophenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.05 (1H, dd, J = 8.3,1.7 Hz), 7.18-7.26 (3H, m), 7.34-7.40 (2H, m), 7.48-7.53 (2H , m), 7.57-7.63 (2H, m), 7.98 (1H, d, J = 8.3Hz), 9.50-9.70 (1H, broad), 13.00-13.30 (1H, broad).

4- (2-Chlorophenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.81 (1H, dd, J = 8.3, 1.7 Hz), 7.04 (1H, d, J = 1.5 Hz), 7.17-7.23 (2H, m), 7.30- 7.35 (2H, m), 7.38-7.42 (3H, m), 7.52-7.57 (1H, m), 7.97 (1H, d, J = 8.3Hz), 9.60 (1H, s).

4- (3,4-Dimethoxyphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.78 (3H, s), 3.80 (3H, s), 6.99-7.27 (7H, m), 7.33-7.40 (2H, m), 7.94 (1H, d , J = 8.3Hz), 9.61 (1H, s), 13.04 (1H, s).

2- (4-Fluoroanilino) -4- (4-isopropoxyphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.27 (6H, d, J = 6.1 Hz), 4.64 (1H, sep, J = 6.1 Hz), 6.95-7.00 (2H, m), 7.01 (1H, dd, J = 8.3,1.7Hz), 7.19-7.26 (3H, m), 7.34-7.39 (2H, m), 7.46-7.51 (2H, m), 7.94 (1H, d, J = 8.6Hz), 9.60 (1H, s), 13.01 (1H, s).

2- (4-Fluoroanilino) -4- (3-nitrophenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.15 (1H, dd, J = 8.3,1.7 Hz), 7.19-7.26 (2H, m), 7.33 (1H, d, J = 1.4 Hz), 7.35 7.42 (2H, m), 7.75 (1H, t, J = 8.0Hz), 8.00-8.07 (2H, m), 8.21-8.26 (1H, m), 8.33 (1H, t, J = 1.9Hz), 9.60 -9.80 (1H, broad), 13.00-13.04 (1H, broad).

2- (4-Fluoroanilino) -4- (4-nitrophenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.14 (1H, dd, J = 8.2,1.6 Hz), 7.19-7.26 (2H, m), 7.33 (1H, d, J = 1.4 Hz), 7.36 7.42 (2H, m), 7.86 (2H, d, J = 9.0Hz), 8.03 (1H, d, J = 8.3Hz), 8.28 (2H, d, J = 9.0Hz), 9.65 (1H, s), 13.10-13.40 (1H, broad).

4- (2,3-Dimethylphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.09 (3H, s), 2.26 (3H, s), 6.68 (1H, dd, J = 8.1, 1.5 Hz), 6.86 (1H, d, J = 1.5 H), 6.99 (1H, d, J = 6.8Hz), 7.10 (1H, t, J = 7.6Hz), 7.12-7.22 (3H, m), 7.27-7.34 (2H, m), 7.94 (1H, d , J = 8.3Hz), 9.59 (1H, s), 13.07 (1H, s).

4- (3,4-Dimethylphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.23 (3H, s), 2.26 (3H, s), 7.02 (1H, d, J = 8.3 Hz), 7.17-7.29 (5H, m), 7.32 7.39 (3H, m), 7.95 (1H, d, J = 8.3Hz), 9.57-9.65 (1H, broad), 12.90-13.20 (1H, broad).

4- (2,6-Dimethylphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 1.99 (6H, s), 6.54 (1H, dd, J = 8.0, 1.5 Hz), 6.71 (1H, d, J = 1.2 Hz), 7.05-7.10 ( 2H, m), 7.11-7.22 (3H, m), 7.23-7.29 (2H, m), 7.97 (1H, d, J = 8.1Hz), 9.59 (1H, s), 13.08 (1H, s).

2- (4-Fluoroanilino) -4- (2-hydroxyphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.85 (1H, t, J = 7.4 Hz), 6.91 (1H, d, J = 7.8 Hz), 6.94 (1H, dd, J = 8.3, 1.5 Hz) , 7.14-7.21 (3H, m), 7.24 (1H, dd, J = 7.6,1.4Hz), 7.29-7.37 (3H, m), 7.91 (1H, d, J = 8.3Hz), 9.56 (1H, s ), 9.63 (1H, s), 12.99 (1H, s).

4- (3,5-Dimethyl-4-hydroxyphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.19 (6H, s), 6.97 (1H, dd, J = 8.3, 1.7 Hz), 7.13 (2H, s), 7.19-7.25 (3H, m), 7.31-7.37 (2H, m), 7.91 (1H, d, J = 8.3Hz), 8.48 (1H, s), 9.59 (1H, s), 12.96 (1H, s).

4- (3-Chloro-4-methoxyphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.88 (3H, s), 7.04 (1H, dd, J = 8.3, 1.7 Hz), 7.19-7.25 (4H, m), 7.34-7.40 (2H, m ), 7.52 (1H, dd, J = 8.6, 2.3Hz), 7.64 (1H, d, J = 2.2Hz), 7.95 (1H, d, J = 8.3Hz), 9.62 (1H, s), 13.09 (1H , s).

2- (4-Fluoroanilino) -4- (3-methylphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.35 (3H, s), 7.03 (1H, dd, J = 8.3, 1.7 Hz), 7.18-7.26 (4H, m), 7.31-7.40 (5H, m ), 7.97 (1H, d, J = 8.3Hz), 9.50-9.70 (1H, broad), 12.90-13.20 (1H, broad).

2- (4-Fluoroanilino) -4- (2- (trifluoromethoxy) phenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.85 (1H, dd, J = 8.2, 1.5 Hz), 7.06-7.11 (1H, m), 7.16-7.24 (2H, m), 7.27-7.35 (2H , m), 7.42-7.56 (4H, m), 7.98 (1H, d, J = 8.2Hz), 9.57 (1H, s), 13.10-13.30 (1H, broad).

2- (4-Fluoroanilino) -4- (3- (trifluoromethoxy) phenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.08 (1H, dd, J = 8.4,1.6 Hz), 7.18-7.30 (3H, m), 7.34-7.44 (3H, m), 7.52-7.64 (3H , m), 7.99 (1H, d, J = 8.4Hz), 9.66 (1H, s), 12.90-13.30 (1H, broad).

2- (4-Fluoroanilino) -4- (4- (trifluoromethoxy) phenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.06 (1H, dd, J = 8.3,1.7 Hz), 7.18-7.28 (3H, m), 7.33-7.47 (4H, m), 7.67-7.74 (2H , m), 7.99 (1H, d, J = 8.3Hz), 9.63 (1H, s), 13.15 (1H, s).

2- (4-Fluoroanilino) -4- (2-oxo-2,3-dihydro-1H-indol-5-yl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.51 (2H, s), 6.87 (1H, d, J = 8.0 Hz), 6.99 (1H, dd, J = 8.5, 1.6 Hz), 7.18-7.26 ( 3H, m), 7.32-7.44 (4H, m), 7.94 (1H, d, J = 8.5Hz), 9.60 (1H, s), 10.48 (1H, s), 13.01 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾアート79mgのトルエン1.6mL溶液に、室温でエタノール0.60mL、水0.30mL、５−ブロモベンゾチオフェン61mg、炭酸水素ナトリウム48mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）11mgを加え、6時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、ｔｅｒｔ−ブチル＝４−（ベンゾチオフェン−５−イル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（ベンゾチオフェン−５−イル）−２−（４−フルオロアニリノ）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；80-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の４−（ベンゾチオフェン−５−イル）−２−（４−フルオロアニリノ）安息香酸16mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.13(1H,dd,J=8.3,1.7Hz),7.19-7.27(2H,m),7.34-7.43(3H,m),7.52(1H,d,J=5.6Hz),7.56(1H,dd,J=8.5,1.6Hz),7.81(1H,d,J=5.6Hz),8.00(1H,d,J=8.3Hz),8.07(1H,d,J=8.5Hz),8.10(1H,d,J=1.6Hz),9.66(1H,s),13.10(1H,s).Example 224

To a 1.6 mL toluene solution of 79 mg tert-butyl = 2- (4-fluoroanilino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate, At room temperature, 0.60 mL of ethanol, 0.30 mL of water, 61 mg of 5-bromobenzothiophene, 48 mg of sodium hydrogen carbonate and 11 mg of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was heated to reflux for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 5: 1], and tert-butyl = 4- (benzothiophen-5-yl)- 2- (4-Fluoroanilino) benzoate was obtained.
To the obtained tert-butyl = 4- (benzothiophen-5-yl) -2- (4-fluoroanilino) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 80-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 4- (benzothiophene) as a yellow solid. 16 mg of -5-yl) -2- (4-fluoroanilino) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.13 (1H, dd, J = 8.3,1.7 Hz), 7.19-7.27 (2H, m), 7.34-7.43 (3H, m), 7.52 (1H, d , J = 5.6Hz), 7.56 (1H, dd, J = 8.5,1.6Hz), 7.81 (1H, d, J = 5.6Hz), 8.00 (1H, d, J = 8.3Hz), 8.07 (1H, d , J = 8.5Hz), 8.10 (1H, d, J = 1.6Hz), 9.66 (1H, s), 13.10 (1H, s).

Examples 225-231
In the same manner as in Example 224, the compounds shown in Table 33 were obtained.

4- (Benzofuran-5-yl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.00 (1H, dd, J = 2.2, 0.7 Hz), 7.09 (1H, dd, J = 8.3, 1.7 Hz), 7.19-7.27 (2H, m), 7.28-7.32 (1H, m), 7.35-7.42 (2H, m), 7.51 (1H, dd, J = 8.7,1.8Hz), 7.66 (1H, d, J = 8.7Hz), 7.86 (1H, d, J = 1.4Hz), 7.98 (1H, d, J = 8.3Hz), 8.04 (1H, d, J = 2.2Hz), 9.64 (1H, s), 12.95-13.20 (1H, broad).

2- (4-Fluoroanilino) -4- (quinoxalin-6-yl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.21-7.30 (3H, m), 7.39-7.47 (3H, m), 8.06 (1H, d, J = 8.0 Hz), 8.09 (1H, dd, J = 8.8, 2.0Hz), 8.18 (1H, d, J = 8.8Hz), 8.26 (1H, d, J = 2.0Hz), 8.94-9.01 (2H, m), 9.67 (1H, s).

4- (5-Chloro-2-methylphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.17 (3H, s), 6.73 (1H, dd, J = 8.1, 1.6 Hz), 6.86-6.90 (1H, m), 7.16-7.24 (3H, m ), 7.28-7.36 (4H, m), 7.95 (1H, d, J = 8.1Hz), 9.60 (1H, s), 13.14 (1H, s).

4- (5-Chloro-2-methoxyphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.78 (3H, s), 6.87 (1H, dd, J = 8.2, 1.7 Hz), 7.13 (1H, d, J = 8.8 Hz), 7.17-7.26 ( 3H, m), 7.29-7.36 (3H, m), 7.40 (1H, dd, J = 8.8, 2.7Hz), 7.92 (1H, d, J = 8.2Hz), 9.54 (1H, s), 13.10 (1H , s).

4- (3-Chloro-4-hydroxyphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.98-7.06 (2H, m), 7.17-7.27 (3H, m), 7.32-7.41 (3H, m), 7.54 (1H, d, J = 2.2Hz ), 7.93 (1H, d, J = 8.3Hz), 9.60 (1H, s), 10.44 (1H, s), 13.05 (1H, s).

4- (3-Chloro-4-methylphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.35 (3H, s), 7.05 (1H, dd, J = 8.3, 1.7 Hz), 7.18-7.26 (3H, m), 7.33-7.47 (4H, m ), 7.60 (1H, s), 7.97 (1H, d, J = 8.3Hz), 9.62 (1H, s), 13.14 (1H, s).

4- (3-Chloro-2-methylphenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.22 (3H, s), 6.72 (1H, dd, J = 8.3, 1.6 Hz), 6.86-6.91 (1H, m), 7.13-7.36 (6H, m ), 7.45 (1H, dd, J = 8.1,1.0Hz), 7.96 (1H, d, J = 8.3Hz), 9.62 (1H, s), 13.05-13.25 (1H, broad).

メチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、４−（アセトアミド）フェニルボロン酸77mg、炭酸ナトリウム69mgおよびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）31mgを加え、90℃で12時間攪拌した。反応混合物を室温まで冷却した後、４−（アセトアミド）フェニルボロン酸39mgおよび炭酸ナトリウム22mgを加え、95℃で14時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、エタノール2.0mLおよび2.0mol/L水酸化ナトリウム水溶液1.0mLを加え、室温で1時間攪拌した。反応混合物に6.0mol/L塩酸0.50mL、水3.0mLおよび酢酸エチル4.0mLを加えた。有機層を分取し、減圧下で溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；40-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の４−（４−（アセトアミド）フェニル）−２−（４−フルオロアニリノ）安息香酸14mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.05(3H,s),7.04(1H,d,J=8.1Hz),7.18-7.28(3H,m),7.33-7.41(2H,m),7.49-7.56(2H,m),7.61-7.70(2H,m),7.95(1H,d,J=8.3Hz),9.62(1H,s),10.07(1H,s).Example 232

Methyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in N, N-dimethylacetamide 2.5 mL solution, 4- (acetamido) phenylboronic acid 77 mg, sodium carbonate 69 mg and polymer supported di (acetate) 31 mg of dicyclohexylphenylphosphine palladium (II) was added and stirred at 90 ° C. for 12 hours. After cooling the reaction mixture to room temperature, 39 mg of 4- (acetamido) phenylboronic acid and 22 mg of sodium carbonate were added, and the mixture was stirred at 95 ° C. for 14 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, ethanol (2.0 mL) and 2.0 mol / L aqueous sodium hydroxide solution (1.0 mL) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 6.0 mol / L hydrochloric acid 0.50 mL, water 3.0 mL, and ethyl acetate 4.0 mL. The organic layer was separated and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography [eluent: 40-100% acetonitrile / 0.1% aqueous trifluoroacetic acid] to give 4- (4- (acetamido) phenyl) -2- as a pale yellow solid. 14 mg of (4-fluoroanilino) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.05 (3H, s), 7.04 (1H, d, J = 8.1 Hz), 7.18-7.28 (3H, m), 7.33-7.41 (2H, m), 7.49-7.56 (2H, m), 7.61-7.70 (2H, m), 7.95 (1H, d, J = 8.3Hz), 9.62 (1H, s), 10.07 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのトルエン2.1mL溶液に、室温でエタノール0.60mL、水0.30mL、１−メチル−５−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インドール84mg、炭酸水素ナトリウム69mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）16mgを加え、4時間加熱還流した。反応混合物を室温まで冷却した後、トルエンおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（１−メチル−１H−インドール−５−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（１−メチル−１H−インドール−５−イル）ベンゾアートに、ジオキサン1.5mL、メタノール1.5mLおよび2.0mol/L水酸化ナトリウム水溶液0.29mLを加え、50℃で2時間攪拌した。反応混合物を室温まで冷却した後、2.0mol/L水酸化ナトリウム水溶液0.20mLを加え、55℃で1時間30分間攪拌した。次いで、2.0mol/L水酸化ナトリウム水溶液0.29mLを加え、55℃で1時間20分間攪拌し、2.0mol/L水酸化ナトリウム水溶液0.29mLを加え、55℃で1時間攪拌し、2.0mol/L水酸化ナトリウム水溶液0.29mLを加え、55℃で1時間攪拌した。反応混合物を室温まで冷却した後、トルエンおよび水を加えた。水層を分取し、トルエンで洗浄後、1.0mol/L塩酸でpH3.4に調整し、酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、淡黄色固体の２−（４−フルオロアニリノ）−４−（１−メチル−１H−インドール−５−イル）安息香酸37mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.80(3H,m),6.46-6.49(1H,m),7.08(1H,dd,J=8.3,1.7Hz),7.18-7.25(2H,m),7.32(1H,d,J=1.4Hz),7.33-7.40(4H,m),7.49(1H,d,J=8.6Hz),7.75(1H,d,J=1.2Hz),7.96(1H,d,J=8.3Hz).Example 233

To a solution of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate (0.10 g) in toluene (2.1 mL) at room temperature is ethanol 0.60 mL, water 0.30 mL, 1-methyl-5- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (84 mg), sodium hydrogen carbonate (69 mg) and tetrakis (triphenylphosphine) palladium (0) (16 mg) were added, and the mixture was heated to reflux for 4 hours. After the reaction mixture was cooled to room temperature, toluene and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(1-Methyl-1H-indol-5-yl) benzoate was obtained.
The resulting tert-butyl = 2- (4-fluoroanilino) -4- (1-methyl-1H-indol-5-yl) benzoate was added with 1.5 mL of dioxane, 1.5 mL of methanol and 2.0 mol / L hydroxylated. Sodium aqueous solution 0.29mL was added and it stirred at 50 degreeC for 2 hours. After the reaction mixture was cooled to room temperature, 0.20 mL of a 2.0 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at 55 ° C. for 1 hour and 30 minutes. Then, 0.29 mL of 2.0 mol / L sodium hydroxide aqueous solution was added and stirred at 55 ° C for 1 hour and 20 minutes, 0.29 mL of 2.0 mol / L sodium hydroxide aqueous solution was added and stirred at 55 ° C for 1 hour, and 2.0 mol / L Sodium hydroxide aqueous solution 0.29mL was added and it stirred at 55 degreeC for 1 hour. After the reaction mixture was cooled to room temperature, toluene and water were added. The aqueous layer was separated, washed with toluene, adjusted to pH 3.4 with 1.0 mol / L hydrochloric acid, and ethyl acetate was added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 37 mg of 2- (4-fluoroanilino) -4- (1-methyl-1H-indol-5-yl) benzoic acid as a pale yellow solid. Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.80 (3H, m), 6.46-6.49 (1H, m), 7.08 (1H, dd, J = 8.3, 1.7 Hz), 7.18-7.25 (2H, m ), 7.32 (1H, d, J = 1.4Hz), 7.33-7.40 (4H, m), 7.49 (1H, d, J = 8.6Hz), 7.75 (1H, d, J = 1.2Hz), 7.96 (1H , d, J = 8.3Hz).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾアート60mgのトルエン1.6mL溶液に、室温でエタノール0.60mL、水0.30mL、４−ブロモインドール0.034mL、炭酸水素ナトリウム30mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）8.4mgを加え、窒素雰囲気下、5時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（１Ｈ−インドール−４−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（１Ｈ−インドール−４−イル）ベンゾアートに、メタノール1.0mL、ジオキサン1.0mLおよび2.0mol/L水酸化ナトリウム水溶液0.23mLを加え、50℃で2時間30分間、次いで、2.0mol/L水酸化ナトリウム水溶液0.23mLを加え、50℃で4時間攪拌し、さらに、2.0mol/L水酸化ナトリウム水溶液0.23mLを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、トルエンおよび水を加えた。水層を分取し、トルエンで洗浄後、1.0mol/L塩酸でpH3.0に調整し、酢酸エチルを加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（４−フルオロアニリノ）−４−（１Ｈ−インドール−４−イル）安息香酸23mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.44-6.48(1H,m),7.03-7.09(2H,m),7.12-7.26(3H,m),7.28(1H,d,J=1.2Hz),7.34-7.44(4H,m),8.00(1H,d,J=8.3Hz),9.59(1H,s),11.29(1H,s),12.90-13.15(1H,broad).Example 234

To a solution of 60 mg of tert-butyl = 2- (4-fluoroanilino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate in 1.6 mL of toluene, At room temperature, 0.60 mL of ethanol, 0.30 mL of water, 0.034 mL of 4-bromoindole, 30 mg of sodium bicarbonate and 8.4 mg of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was heated to reflux for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 5: 1], and tert-butyl = 2- (4-fluoroanilino). ) -4- (1H-Indol-4-yl) benzoate was obtained.
To the obtained tert-butyl = 2- (4-fluoroanilino) -4- (1H-indol-4-yl) benzoate, methanol 1.0 mL, dioxane 1.0 mL and 2.0 mol / L aqueous sodium hydroxide solution 0.23 mL 2 hours and 30 minutes at 50 ° C., then add 0.23 mL of 2.0 mol / L aqueous sodium hydroxide solution, stir at 50 ° C. for 4 hours, and further add 0.23 mL of 2.0 mol / L aqueous sodium hydroxide solution, 2 Heated to reflux for hours. After the reaction mixture was cooled to room temperature, toluene and water were added. The aqueous layer was separated, washed with toluene, adjusted to pH 3.0 with 1.0 mol / L hydrochloric acid, and ethyl acetate was added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 23 mg of 2- (4-fluoroanilino) -4- (1H-indol-4-yl) benzoic acid as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.44-6.48 (1H, m), 7.03-7.09 (2H, m), 7.12-7.26 (3H, m), 7.28 (1H, d, J = 1.2Hz ), 7.34-7.44 (4H, m), 8.00 (1H, d, J = 8.3Hz), 9.59 (1H, s), 11.29 (1H, s), 12.90-13.15 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート80mgのＮ，Ｎ−ジメチルアセトアミド2.5mL溶液に、３−（ヒドロキシメチル）フェニルボロン酸50mg、炭酸ナトリウム58mgおよびポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）7.0mgを加え、110℃で19時間攪拌した。反応混合物を室温まで冷却した後、ポリマー担持ジ（アセタート）ジシクロヘキシルフェニルホスフィンパラジウム（II）7.0mgを加え、110℃で30時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（３−（ヒドロキシメチル）フェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（３−（ヒドロキシメチル）フェニル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；70-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、淡黄色固体の２−（４−フルオロアニリノ）−４−（３−（ヒドロキシメチル）フェニル）安息香酸7.7mgを得た。
¹H-NMR(DMSO-d₆)δ値：4.53(2H,d,J=5.6Hz),5.23(1H,t,J=5.6Hz),7.04(1H,dd,J=8.3,1.6Hz),7.19-7.28(3H,m),7.31-7.45(5H,m),7.51(1H,s),7.98(1H,d,J=8.3Hz),9.62(1H,s).Example 235

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 80 mg in N, N-dimethylacetamide 2.5 mL solution, 3- (hydroxymethyl) phenylboronic acid 50 mg, sodium carbonate 58 mg and polymer supported di 7.0 mg of (acetate) dicyclohexylphenylphosphine palladium (II) was added and stirred at 110 ° C. for 19 hours. After cooling the reaction mixture to room temperature, 7.0 mg of polymer-supported di (acetate) dicyclohexylphenylphosphine palladium (II) was added, and the mixture was stirred at 110 ° C. for 30 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(3- (Hydroxymethyl) phenyl) benzoate was obtained.
To the obtained tert-butyl = 2- (4-fluoroanilino) -4- (3- (hydroxymethyl) phenyl) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 70-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4 -Fluoroanilino) -4- (3- (hydroxymethyl) phenyl) benzoic acid 7.7 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 4.53 (2H, d, J = 5.6Hz), 5.23 (1H, t, J = 5.6Hz), 7.04 (1H, dd, J = 8.3,1.6Hz) 7.19-7.28 (3H, m), 7.31-7.45 (5H, m), 7.51 (1H, s), 7.98 (1H, d, J = 8.3Hz), 9.62 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのトルエン1.6mL溶液に、室温でエタノール0.60mL、水0.30mL、２−イソプロポキシフェニルボロン酸0.048mL、炭酸水素ナトリウム48mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）11mgを加え、6時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−イソプロポキシフェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−イソプロポキシフェニル）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；80-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（４−フルオロアニリノ）−４−（２−イソプロポキシフェニル）安息香酸16mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.11(6H,d,J=6.0Hz),4.57(1H,sep,J=6.0Hz),6.86(1H,dd,J=8.3,1.6Hz),6.94-7.01(1H,m),7.07(1H,d,J=8.0Hz),7.16-7.36(7H,m),7.91(1H,d,J=8.3Hz),9.53(1H,s),13.00(1H,s).Example 236

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in toluene 1.6 mL solution at room temperature with ethanol 0.60 mL, water 0.30 mL, 2-isopropoxyphenylboronic acid 0.048 mL, sodium bicarbonate 48 mg and tetrakis (triphenylphosphine) palladium (0) 11 mg were added, and the mixture was heated to reflux for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 5: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(2-Isopropoxyphenyl) benzoate was obtained.
To the obtained tert-butyl = 2- (4-fluoroanilino) -4- (2-isopropoxyphenyl) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 80-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4- 16 mg of fluoroanilino) -4- (2-isopropoxyphenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.11 (6H, d, J = 6.0 Hz), 4.57 (1H, sep, J = 6.0 Hz), 6.86 (1H, dd, J = 8.3, 1.6 Hz) , 6.94-7.01 (1H, m), 7.07 (1H, d, J = 8.0Hz), 7.16-7.36 (7H, m), 7.91 (1H, d, J = 8.3Hz), 9.53 (1H, s), 13.00 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート70mgのトルエン1.6mL溶液に、室温でエタノール0.60mL、水0.30mL、４−（ジメチルアミノ）フェニルボロン酸47mg、炭酸水素ナトリウム48mgおよびテトラキス（トリフェニルホスフィン）パラジウム（０）11mgを加え、6時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝４−（４−(ジメチルアミノ）フェニル)−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（４−(ジメチルアミノ）フェニル)−２−（４−フルオロアニリノ）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.5に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の４−（４−（ジメチルアミノ）フェニル）−２−（４−フルオロアニリノ）安息香酸33mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.93(6H,s),6.73-6.80(2H,m),7.00(1H,dd,J=8.4,1.7Hz),7.18-7.26(3H,m),7.32-7.39(2H,m),7.40-7.46(2H,m),7.90(1H,d,J=8.4Hz),9.59(1H,s),12.92(1H,s).Example 237

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 70 mg in toluene 1.6 mL solution at room temperature 0.60 mL ethanol, water 0.30 mL, 4- (dimethylamino) phenylboronic acid 47 mg, hydrogen carbonate Sodium (48 mg) and tetrakis (triphenylphosphine) palladium (0) (11 mg) were added, and the mixture was heated to reflux for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 4- (4- (dimethylamino ) Phenyl) -2- (4-fluoroanilino) benzoate was obtained.
To the obtained tert-butyl 4- (4- (dimethylamino) phenyl) -2- (4-fluoroanilino) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and the pH was adjusted to 6.5 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 33 mg of 4- (4- (dimethylamino) phenyl) -2- (4-fluoroanilino) benzoic acid as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.93 (6H, s), 6.73-6.80 (2H, m), 7.00 (1H, dd, J = 8.4,1.7Hz), 7.18-7.26 (3H, m ), 7.32-7.39 (2H, m), 7.40-7.46 (2H, m), 7.90 (1H, d, J = 8.4Hz), 9.59 (1H, s), 12.92 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.20gのトルエン4.0mL溶液に、室温でエタノール1.2mL、水0.60mL、４−（ヒドロキシメチル）フェニルボロン酸91mg、炭酸水素ナトリウム0.12gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）35mgを加え、窒素雰囲気下、6時間加熱還流した。反応混合物を室温まで冷却した後、水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、淡黄色固体のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４−（ヒドロキシメチル）フェニル）ベンゾアート64mgを得た。
¹H-NMR(DMSO-d₆)δ値：1.58(9H,s),4.50-4.54(2H,m),5.22(1H,t,J=5.6Hz),7.06(1H,dd,J=8.3,1.7Hz),7.18-7.25(2H,m),7.26(1H,d,J=1.7Hz),7.34-7.41(4H,m),7.50-7.54(2H,m),7.92(1H,d,J=8.3Hz),9.37(1H,s).Example 238

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.20 g in toluene 4.0 mL solution at room temperature with ethanol 1.2 mL, water 0.60 mL, 4- (hydroxymethyl) phenylboronic acid 91 mg, carbonic acid Sodium hydrogen 0.12 g and tetrakis (triphenylphosphine) palladium (0) 35 mg were added, and the mixture was heated to reflux for 6 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: hexane: ethyl acetate = 2: 1], and tert-butyl 2- (4 -Fluoroanilino) -4- (4- (hydroxymethyl) phenyl) benzoate 64 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.58 (9H, s), 4.50-4.54 (2H, m), 5.22 (1H, t, J = 5.6 Hz), 7.06 (1H, dd, J = 8.3 1.7Hz), 7.18-7.25 (2H, m), 7.26 (1H, d, J = 1.7Hz), 7.34-7.41 (4H, m), 7.50-7.54 (2H, m), 7.92 (1H, d, J = 8.3Hz), 9.37 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４−（ヒドロキシメチル）フェニル）ベンゾアート64mgのトリフルオロ酢酸5.0mL溶液を室温で1時間攪拌した。減圧下で溶媒を留去し、得られた残留物に、ジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、淡黄色固体の２−（４−フルオロアニリノ）−４−（４−（ヒドロキシメチル）フェニル）安息香酸2.0mgを得た。
¹H-NMR(DMSO-d₆)δ値：4.52(2H,d,J=4.4Hz),5.20-5.26(1H,m),7.05(1H,d,J=8.3Hz),7.15-7.30(3H,m),7.32-7.42(4H,m),7.53(2H,d,J=7.8Hz),7.97(1H,d,J=8.3Hz),9.56-9.74(1H,broad).Example 239

A solution of 64 mg of tert-butyl = 2- (4-fluoroanilino) -4- (4- (hydroxymethyl) phenyl) benzoate 64 mg in trifluoroacetic acid was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, diisopropyl ether and hexane were added to the obtained residue, the solid was collected by filtration, and 2- (4-fluoroanilino) -4- (4- (4- ( 2.0 mg of hydroxymethyl) phenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 4.52 (2H, d, J = 4.4 Hz), 5.20-5.26 (1H, m), 7.05 (1H, d, J = 8.3 Hz), 7.15-7.30 ( 3H, m), 7.32-7.42 (4H, m), 7.53 (2H, d, J = 7.8Hz), 7.97 (1H, d, J = 8.3Hz), 9.56-9.74 (1H, broad).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾアート0.15gのトルエン3.0mL溶液に、室温でエタノール0.90mL、水0.45mL、４−ブロモベンゼンスルホンアミド85mg、炭酸水素ナトリウム0.10gおよびテトラキス（トリフェニルホスフィン）パラジウム（０）21mgを加え、窒素雰囲気下、2時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、ｔｅｒｔ−ブチル＝４−（４−（アミノスルホニル）フェニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（４−（アミノスルホニル）フェニル）−２−（４−フルオロアニリノ）ベンゾアートのトリフルオロ酢酸3.0mL溶液を室温で30分間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、淡黄色固体の４−（４−（アミノスルホニル）フェニル）−２−（４−フルオロアニリノ）安息香酸20mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.10(1H,d,J=7.8Hz),7.18-7.26(2H,m),7.30-7.40(5H,m),7.74-7.81(2H,m),7.84-7.90(2H,m),8.01(1H,d,J=8.0Hz),9.63-9.68(1H,broad),13.16-13.24(1H,broad).Example 240

tert-Butyl 2- (4-fluoroanilino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate 0.15 g in a toluene 3.0 mL solution At room temperature, 0.90 mL of ethanol, 0.45 mL of water, 85 mg of 4-bromobenzenesulfonamide, 0.10 g of sodium bicarbonate and 21 mg of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 2: 1], and tert-butyl = 4- (4- (aminosulfonyl) phenyl). -2- (4-Fluoroanilino) benzoate was obtained.
The obtained tert-butyl = 4- (4- (aminosulfonyl) phenyl) -2- (4-fluoroanilino) benzoate in 3.0 mL of trifluoroacetic acid was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, the solid was collected by filtration, and a pale yellow solid 4- (4- (aminosulfonyl) phenyl) -2- (4-fluoroanis Reno) 20 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.10 (1H, d, J = 7.8 Hz), 7.18-7.26 (2H, m), 7.30-7.40 (5H, m), 7.74-7.81 (2H, m ), 7.84-7.90 (2H, m), 8.01 (1H, d, J = 8.0Hz), 9.63-9.68 (1H, broad), 13.16-13.24 (1H, broad).

実施例２４０と同様にして、以下の化合物を得た。
４−（３−（アミノカルボニル）フェニル）−２−（４−フルオロアニリノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：7.12(1H,dd,J=8.3,1.7Hz),7.18-7.25(2H,m),7.32(1H,d,J=1.7Hz),7.34-7.46(3H,m),7.53(1H,t,J=7.7Hz),7.68-7.74(1H,m),7.85-7.90(1H,m),8.00(1H,d,J=8.3Hz),8.04-8.12(2H,m),9.64(1H,s),13.12-13.17(1H,broad).Example 241

In the same manner as in Example 240, the following compound was obtained.
4- (3- (aminocarbonyl) phenyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.12 (1H, dd, J = 8.3,1.7 Hz), 7.18-7.25 (2H, m), 7.32 (1H, d, J = 1.7 Hz), 7.34 7.46 (3H, m), 7.53 (1H, t, J = 7.7Hz), 7.68-7.74 (1H, m), 7.85-7.90 (1H, m), 8.00 (1H, d, J = 8.3Hz), 8.04 -8.12 (2H, m), 9.64 (1H, s), 13.12-13.17 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのトルエン3.0mL溶液に、室温で１Ｈ−インドール48mg、リン酸三カリウム0.12g、トリス（ジベンジリデンアセトン）ジパラジウム（０）8.0mg、トリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート2.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.0mgを加え、2時間加熱還流した。反応混合物を室温まで冷却した後、トリス（ジベンジリデンアセトン）ジパラジウム（０）8.0mg、トリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート2.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.0mgを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、トリス（ジベンジリデンアセトン）ジパラジウム（０）8.0mg、トリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート2.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.0mgを加え、7時間加熱還流した。反応混合物を室温まで冷却した後、トルエンおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（１Ｈ−インドール−１−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（１Ｈ−インドール−１−イル）ベンゾアートに、ジオキサン1.5mL、メタノール1.5mLおよび2.0mol/L水酸化ナトリウム水溶液0.41mLを加え、40℃で5時間攪拌した。反応混合物を室温まで冷却した後、2.0mol/L水酸化ナトリウム水溶液0.41mLを加え、50℃で3時間攪拌した。反応混合物を室温まで冷却した後、水を加え、1.0mol/L塩酸でpH3.6に調整し、酢酸エチルを加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；60-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（４−フルオロアニリノ）−４−（１Ｈ−インドール−１−イル）安息香酸6.0mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.70(1H,d,J=3.2Hz),7.00(1H,dd,J=8.6,2.2Hz),7.08(1H,d,J=2.2Hz),7.10-7.16(1H,m),7.18-7.27(3H,m),7.40-7.46(2H,m),7.57(1H,d,J=8.3Hz),7.61-7.66(2H,m),8.07(1H,d,J=8.6Hz),9.73(1H,s).Example 242

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.10 g in toluene 3.0 mL solution at room temperature 1H-indole 48 mg, tripotassium phosphate 0.12 g, tris (dibenzylideneacetone) dipalladium (0) 8.0 mg, tri-tert-butylphosphine tetrafluoroborate 2.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 7.0 mg were added, and the mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, 8.0 mg of tris (dibenzylideneacetone) dipalladium (0), 2.0 mg of tri-tert-butylphosphine tetrafluoroborate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6 ′ -Triisopropyl biphenyl 7.0mg was added and it heated and refluxed for 3 hours. After the reaction mixture was cooled to room temperature, 8.0 mg of tris (dibenzylideneacetone) dipalladium (0), 2.0 mg of tri-tert-butylphosphine tetrafluoroborate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6 ′ -Triisopropyl biphenyl 7.0mg was added and it heated and refluxed for 7 hours. After the reaction mixture was cooled to room temperature, toluene and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 5: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(1H-Indol-1-yl) benzoate was obtained.
To the resulting tert-butyl = 2- (4-fluoroanilino) -4- (1H-indol-1-yl) benzoate, dioxane 1.5 mL, methanol 1.5 mL and 2.0 mol / L sodium hydroxide aqueous solution 0.41 mL And stirred at 40 ° C. for 5 hours. After the reaction mixture was cooled to room temperature, 2.01 mL of a 2.0 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, the pH was adjusted to 3.6 with 1.0 mol / L hydrochloric acid, and ethyl acetate was added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse phase silica gel column chromatography [eluent: 60-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino) -4- (1H as a white solid. -Indol-1-yl) benzoic acid 6.0 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.70 (1H, d, J = 3.2 Hz), 7.00 (1H, dd, J = 8.6, 2.2 Hz), 7.08 (1H, d, J = 2.2 Hz) , 7.10-7.16 (1H, m), 7.18-7.27 (3H, m), 7.40-7.46 (2H, m), 7.57 (1H, d, J = 8.3Hz), 7.61-7.66 (2H, m), 8.07 (1H, d, J = 8.6Hz), 9.73 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのトルエン3.0mL溶液に、インドリン0.046mL、炭酸セシウム0.18g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mg、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.0mgおよび酢酸パラジウム1.0mgを加え、2時間加熱還流した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mg、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.0mgおよび酢酸パラジウム1.0mgを加え、3時間加熱還流した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mg、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.0mgおよび酢酸パラジウム1.0mgを加え、7時間加熱還流した。反応混合物を室温まで冷却した後、トルエンおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（インドリン−１−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（インドリン−１−イル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間10分間攪拌した。減圧下で溶媒を留去し、得られた残留物に、酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.5に調整した。有機層を分取し、水および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の２−（４−フルオロアニリノ）−４−（インドリン−１−イル）安息香酸22mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.06(2H,t,J=8.4Hz),3.91(2H,t,J=8.4Hz),6.62(1H,dd,J=8.9,2.0Hz),6.73(1H,d,J=2.0Hz),6.78(1H,t,J=7.1Hz),7.03-7.13(2H,m),7.17-7.27(3H,m),7.32-7.40(2H,m),7.85(1H,d,J=8.9Hz),9.66(1H,s).Example 243

tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.10 g in toluene 3.0 mL solution, indoline 0.046 mL, cesium carbonate 0.18 g, tris (dibenzylideneacetone) dipalladium (0) 3.0 mg 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 7.0 mg and palladium acetate 1.0 mg were added, and the mixture was heated to reflux for 2 hours. Tris (dibenzylideneacetone) dipalladium (0) 3.0 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 7.0 mg and palladium acetate 1.0 mg were added, and the mixture was heated to reflux for 3 hours. Tris (dibenzylideneacetone) dipalladium (0) 3.0 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 7.0 mg and palladium acetate 1.0 mg were added, and the mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, toluene and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -(Indolin-1-yl) benzoate was obtained.
To the obtained tert-butyl = 2- (4-fluoroanilino) -4- (indoline-1-yl) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours and 10 minutes. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the obtained residue, and the pH was adjusted to 6.5 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 22 mg of 2- (4-fluoroanilino) -4- (indoline-1-yl) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.06 (2H, t, J = 8.4 Hz), 3.91 (2H, t, J = 8.4 Hz), 6.62 (1H, dd, J = 8.9, 2.0 Hz) , 6.73 (1H, d, J = 2.0Hz), 6.78 (1H, t, J = 7.1Hz), 7.03-7.13 (2H, m), 7.17-7.27 (3H, m), 7.32-7.40 (2H, m ), 7.85 (1H, d, J = 8.9Hz), 9.66 (1H, s).

実施例２４３と同様にして、以下の化合物を得た。
２−（４−フルオロアニリノ）−４−（１，２，３，４−テトラヒドロイソキノリン−２−イル）安息香酸
¹H-NMR(DMSO-d₆)δ値：2.88(2H,t,J=6.0Hz),3.51(2H,t,J=6.0Hz),4.42(2H,s),6.45(1H,dd,J=9.0,2.2Hz),6.48(1H,d,J=2.2Hz),7.16-7.23(6H,m),7.27-7.33(2H,m),7.75(1H,d,J=9.0Hz),9.70(1H,s).Example 244

In the same manner as in Example 243, the following compound was obtained.
2- (4-Fluoroanilino) -4- (1,2,3,4-tetrahydroisoquinolin-2-yl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.88 (2H, t, J = 6.0 Hz), 3.51 (2H, t, J = 6.0 Hz), 4.42 (2H, s), 6.45 (1H, dd, J = 9.0,2.2Hz), 6.48 (1H, d, J = 2.2Hz), 7.16-7.23 (6H, m), 7.27-7.33 (2H, m), 7.75 (1H, d, J = 9.0Hz), 9.70 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.30gのトルエン3.0mL溶液に、室温で２−ニトロアニリン0.17g、炭酸セシウム0.53g、トリス（ジベンジリデンアセトン）ジパラジウム（０）8.0mg、酢酸パラジウム4.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル20mgを加え、窒素雰囲気下、2時間加熱還流した。トリス（ジベンジリデンアセトン）ジパラジウム（０）8.0mg、酢酸パラジウム4.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル20mgを加え、3時間加熱還流した。トリス（ジベンジリデンアセトン）ジパラジウム（０）8.0mg、酢酸パラジウム4.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル20mgを加え、7時間加熱還流した。反応混合物を室温まで冷却した後、トルエン、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、黄色固体のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−ニトロアニリノ）ベンゾアート0.35gを得た。
¹H-NMR(CDCl₃)δ値：1.62(9H,s),6.57(1H,dd,J=8.8,2.2Hz),6.80(1H,d,J=2.2Hz),6.81-6.87(1H,m),7.02-7.08(2H,m),7.17-7.24(2H,m),7.37-7.41(2H,m),7.91(1H,d,J=8.8Hz),8.14-8.19(1H,m),9.29(1H,s),9.57(1H,s).Example 245

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.30 g in toluene 3.0 mL, 2-nitroaniline 0.17 g, cesium carbonate 0.53 g, tris (dibenzylideneacetone) dipalladium at room temperature (0) 8.0 mg, palladium acetate 4.0 mg, and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 20 mg were added, and the mixture was heated to reflux for 2 hours under a nitrogen atmosphere. Tris (dibenzylideneacetone) dipalladium (0) 8.0 mg, palladium acetate 4.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 20 mg were added, and the mixture was heated to reflux for 3 hours. Tris (dibenzylideneacetone) dipalladium (0) 8.0 mg, palladium acetate 4.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 20 mg were added, and the mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, toluene, ethyl acetate and 10% aqueous citric acid solution were added, and insoluble materials were removed by filtration. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: hexane: ethyl acetate = 10: 1], and tert-butyl 2- (4- 0.35 g of fluoroanilino) -4- (2-nitroanilino) benzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.62 (9H, s), 6.57 (1H, dd, J = 8.8, 2.2 Hz), 6.80 (1H, d, J = 2.2 Hz), 6.81-6.87 (1H, m), 7.02-7.08 (2H, m), 7.17-7.24 (2H, m), 7.37-7.41 (2H, m), 7.91 (1H, d, J = 8.8Hz), 8.14-8.19 (1H, m) , 9.29 (1H, s), 9.57 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−ニトロアニリノ）ベンゾアート0.35gのテトラヒドロフラン10mLおよび酢酸エチル5.0mL混液に、10％パラジウム−炭素74mgを加え、水素雰囲気下、室温で4時間30分間攪拌後、34℃で4時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、白色固体のｔｅｒｔ−ブチル＝４−（（２−アミノフェニル）アミノ）−２−（４−フルオロアニリノ）ベンゾアート0.15gを得た。
¹H-NMR(CDCl₃)δ値：1.57(9H,s),5.34(1H,s),6.06(1H,dd,J=8.8,2.3Hz),6.31(1H,d,J=2.3Hz),6.70-6.79(2H,m),6.94-7.10(4H,m),7.14-7.20(2H,m),7.77(1H,d,J=8.8Hz),9.57(1H,s).Example 246

tert-Butyl 2- (4-fluoroanilino) -4- (2-nitroanilino) benzoate 0.35 g of tetrahydrofuran 10 mL and ethyl acetate 5.0 mL were mixed with 10% palladium-carbon 74 mg, and hydrogen atmosphere was added at room temperature. The mixture was stirred for 4 hours 30 minutes and then stirred at 34 ° C. for 4 hours. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Hexane is added to the obtained residue, and the solid substance is collected by filtration, and 0.15 g of tert-butyl 4-((2-aminophenyl) amino) -2- (4-fluoroanilino) benzoate as a white solid is obtained. Obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.57 (9H, s), 5.34 (1H, s), 6.06 (1H, dd, J = 8.8, 2.3 Hz), 6.31 (1H, d, J = 2.3 Hz) 6.70-6.79 (2H, m), 6.94-7.10 (4H, m), 7.14-7.20 (2H, m), 7.77 (1H, d, J = 8.8Hz), 9.57 (1H, s).

ｔｅｒｔ−ブチル＝４−（（２−アミノフェニル）アミノ）−２−（４−フルオロアニリノ）ベンゾアート0.15gのエチレングリコールモノメチルエーテル3.0mL溶液に、室温でホルムアミジン酢酸塩0.10gを加え、80℃で6時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、飽和炭酸水素ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、淡赤色固体のｔｅｒｔ−ブチル＝４−（１Ｈ−ベンズイミダゾール−１−イル）−２−（４−フルオロアニリノ）ベンゾアート0.16gを得た。
¹H-NMR(CDCl₃)δ値：1.65(9H,s),6.83(1H,dd,J=8.6,2.2Hz),7.04-7.11(3H,m),7.23-7.28(2H,m),7.30-7.34(2H,m),7.47-7.51(1H,m),7.82-7.86(1H,m),8.05(1H,s),8.10(1H,d,J=8.6Hz),9.68(1H,s).Example 247

To a solution of tert-butyl 4-((2-aminophenyl) amino) -2- (4-fluoroanilino) benzoate 0.15 g in ethylene glycol monomethyl ether 3.0 mL was added formamidine acetate 0.10 g at room temperature, The mixture was stirred at 80 ° C. for 6 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 2: 1], and tert-butyl = 4- (1H 0.16 g of -benzimidazol-1-yl) -2- (4-fluoroanilino) benzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.65 (9H, s), 6.83 (1H, dd, J = 8.6, 2.2 Hz), 7.04-7.11 (3H, m), 7.23-7.28 (2H, m), 7.30-7.34 (2H, m), 7.47-7.51 (1H, m), 7.82-7.86 (1H, m), 8.05 (1H, s), 8.10 (1H, d, J = 8.6Hz), 9.68 (1H, s).

ｔｅｒｔ−ブチル＝４−（１Ｈ−ベンズイミダゾール−１−イル）−２−（４−フルオロアニリノ）ベンゾアート0.16gのトリフルオロ酢酸7.5mL溶液を室温で1時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチルを加え、固形物をろ取し、黄色固体の４−（１Ｈ−ベンズイミダゾール−１−イル）−２−（４−フルオロアニリノ）安息香酸トリフルオロ酢酸塩99mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.10(1H,dd,J=8.5,2.2Hz),7.20-7.26(3H,m),7.36-7.48(4H,m),7.63-7.68(1H,m),7.78-7.83(1H,m),8.14(1H,d,J=8.5Hz),8.91(1H,s),9.79(1H,s).Example 248

A solution of 0.16 g of tert-butyl 4- (1H-benzimidazol-1-yl) -2- (4-fluoroanilino) benzoate in 7.5 mL of trifluoroacetic acid was stirred at room temperature for 1 hour and 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, the solid was collected by filtration, and 4- (1H-benzimidazol-1-yl) -2- (4-fluoroanisine) was obtained as a yellow solid. Reno) 99 mg of benzoic acid trifluoroacetate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.10 (1H, dd, J = 8.5, 2.2 Hz), 7.20-7.26 (3H, m), 7.36-7.48 (4H, m), 7.63-7.68 (1H , m), 7.78-7.83 (1H, m), 8.14 (1H, d, J = 8.5Hz), 8.91 (1H, s), 9.79 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で２−クロロスチレン0.15mL、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.35mLおよび酢酸パラジウム4.6mgを加え、130℃で4時間攪拌した。２−クロロスチレン0.052mL、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.087mLおよび酢酸パラジウム9.2mgを加え、130℃で2時間攪拌した。酢酸パラジウム4.6mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート5.9mgを加え、130℃で8時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２−クロロフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２−クロロフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；85-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の４−（（Ｅ）−２−（２−クロロフェニル）ビニル）−２−（４−フルオロアニリノ）安息香酸4.6mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.08-7.14(1H,m),7.20-7.51(10H,m),7.86-7.95(2H,m),9.59(1H,s),13.06(1H,s).Example 249

tert-Butyl 4-bromo-2- (4-fluoroanilino) benzoate 0.15 g of N, N-dimethylacetamide 3.0 mL solution at room temperature 0.15 mL of 2-chlorostyrene, N, N-dicyclohexylmethylamine 0.35 mL and 4.6 mg of palladium acetate were added, and the mixture was stirred at 130 ° C. for 4 hours. 0.052 mL of 2-chlorostyrene, 0.087 mL of N, N-dicyclohexylmethylamine and 9.2 mg of palladium acetate were added, and the mixture was stirred at 130 ° C. for 2 hours. 4.6 mg of palladium acetate and 5.9 mg of tri-tert-butylphosphine tetrafluoroborate were added, and the mixture was stirred at 130 ° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 4-((E) -2- (2 -Chlorophenyl) vinyl) -2- (4-fluoroanilino) benzoate was obtained.
The obtained tert-butyl 4-((E) -2- (2-chlorophenyl) vinyl) -2- (4-fluoroanilino) benzoate in 10 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 85-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 4-((E ) -2- (2-chlorophenyl) vinyl) -2- (4-fluoroanilino) benzoic acid (4.6 mg) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.08-7.14 (1H, m), 7.20-7.51 (10H, m), 7.86-7.95 (2H, m), 9.59 (1H, s), 13.06 (1H , s).

実施例２４９と同様にして、以下の化合物を得た。
４−（（Ｅ）−２−（３−クロロフェニル）ビニル）−２−（４−フルオロアニリノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：7.11(1H,dd,J=8.4,1.2Hz),7.18-7.42(9H,m),7.57(1H,d,J=7.8Hz),7.74(1H,s),7.90(1H,d,J=8.4Hz),9.60(1H,s),13.03(1H,s).Example 250

In the same manner as in Example 249, the following compound was obtained.
4-((E) -2- (3-chlorophenyl) vinyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.11 (1H, dd, J = 8.4,1.2 Hz), 7.18-7.42 (9H, m), 7.57 (1H, d, J = 7.8 Hz), 7.74 ( 1H, s), 7.90 (1H, d, J = 8.4Hz), 9.60 (1H, s), 13.03 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で３−ブロモトルエン0.058mL、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.17mLおよび（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）6.0mgを加え、90℃で2時間攪拌した。（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）6.0mgを加え、110℃で2時間攪拌した。３−ブロモトルエン0.040mL、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.068mLおよび（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）6.0mgを加え、110℃で4時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−メチルフェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−メチルフェニル）ビニル）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；60-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−メチルフェニル）ビニル）安息香酸を得た。
得られた２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−メチルフェニル）ビニル）安息香酸に、酢酸エチル1.0mL、メタノール1.0mLおよび10％パラジウム−炭素2.0mgを順次加え、水素雰囲気下、室温で3時間30分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、白色固体の２−（４−フルオロアニリノ）−４−（２−（３−メチルフェニル）エチル）安息香酸3.0mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.26(3H,s),2.70-2.84(4H,m),6.56(1H,d,J=7.6Hz),6.83(1H,s),6.93-7.10(7H,m),7.12-7.18(1H,m),7.81(1H,d,J=8.0Hz).Example 251

tert-Butyl-2- (4-fluoroanilino) -4-vinylbenzoate In a solution of 0.10 g of N, N-dimethylacetamide in 3.0 mL, 0.058 mL of 3-bromotoluene, N, N-dicyclohexylmethylamine 0.17 at room temperature mL and 6.0 mg of (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) were added and stirred at 90 ° C. for 2 hours. 6.0 mg of (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) was added and stirred at 110 ° C. for 2 hours. Add 0.040 mL of 3-bromotoluene, 0.068 mL of N, N-dicyclohexylmethylamine and 6.0 mg of (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II), The mixture was stirred at 110 ° C. for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (3-methylphenyl) vinyl) benzoate was obtained.
The obtained tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (3-methylphenyl) vinyl) benzoate in 10 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 60-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino). ) -4-((E) -2- (3-methylphenyl) vinyl) benzoic acid was obtained.
To the obtained 2- (4-fluoroanilino) -4-((E) -2- (3-methylphenyl) vinyl) benzoic acid, 1.0 mL of ethyl acetate, 1.0 mL of methanol and 2.0 mg of 10% palladium-carbon Were sequentially added and stirred at room temperature for 3 hours and 30 minutes in a hydrogen atmosphere. The insoluble material was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain 3.0 mg of 2- (4-fluoroanilino) -4- (2- (3-methylphenyl) ethyl) benzoic acid as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.26 (3H, s), 2.70-2.84 (4H, m), 6.56 (1H, d, J = 7.6 Hz), 6.83 (1H, s), 6.93 7.10 (7H, m), 7.12-7.18 (1H, m), 7.81 (1H, d, J = 8.0Hz).

実施例２５１と同様にして、下記の化合物を得た。
２−（４−フルオロアニリノ）−４−（２−（４−メチルフェニル）エチル）安息香酸
¹H-NMR(DMSO-d₆)δ値：2.26(3H,s),2.69-2.83(4H,m),6.49(1H,dd,J=7.8,1.5Hz),6.81(1H,d,J=1.2Hz),6.91-7.11(8H,m),7.78(1H,d,J=7.8Hz),12.04(1H,s).Example 252

In the same manner as in Example 251, the following compound was obtained.
2- (4-Fluoroanilino) -4- (2- (4-methylphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.26 (3H, s), 2.69-2.83 (4H, m), 6.49 (1H, dd, J = 7.8, 1.5 Hz), 6.81 (1H, d, J = 1.2Hz), 6.91-7.11 (8H, m), 7.78 (1H, d, J = 7.8Hz), 12.04 (1H, s).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で２−フルオロスチレン0.15g、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.35mLおよび酢酸パラジウム4.6mgを加え、130℃で4時間攪拌した。２−フルオロスチレン0.05g、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.087mLおよび（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）4.8mgを加え、130℃で2時間攪拌した。（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）9.6mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート5.9mgを加え、130℃で8時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（２−フルオロフェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（２−フルオロフェニル）ビニル）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸2.0mL、ジオキサン2.0mLおよび10％パラジウム−炭素22mgを順次加え、水素雰囲気下、室温で2時間30分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物に、ジイソプロピルエーテルおよびヘキサンを加え、固形物をろ取し、白色固体の２−（４−フルオロアニリノ）−４−（２−（２−フルオロフェニル）エチル）安息香酸44mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.73-2.91(4H,m),6.57-6.63(1H,m),6.75-6.78(1H,m),7.01-7.30(8H,m),7.80(1H,d,J=8.0Hz).Example 253

To a solution of 0.15 g of tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate in 3.0 mL of N, N-dimethylacetamide at room temperature, 0.15 g of 2-fluorostyrene, N, N-dicyclohexylmethylamine 0.35 mL and 4.6 mg of palladium acetate were added, and the mixture was stirred at 130 ° C. for 4 hours. Add 0.05 g of 2-fluorostyrene, 0.087 mL of N, N-dicyclohexylmethylamine and 4.8 mg of (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II), The mixture was stirred at 130 ° C. for 2 hours. 9.6 mg of (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) and 5.9 mg of tri-tert-butylphosphine tetrafluoroborate were added, Stir for hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (2-fluorophenyl) vinyl) benzoate was obtained.
The obtained tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (2-fluorophenyl) vinyl) benzoate solution in 10 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and 2.0 mL of acetic acid, 2.0 mL of dioxane and 22 mg of 10% palladium-carbon were sequentially added to the obtained residue, and the mixture was stirred at room temperature for 2 hours and 30 minutes in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid substance was collected by filtration to give white solid 2- (4-fluoroanilino) -4- (2- (2-fluorophenyl) ethyl) benzoic acid 44 mg. Got.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.73-2.91 (4H, m), 6.57-6.63 (1H, m), 6.75-6.78 (1H, m), 7.01-7.30 (8H, m), 7.80 (1H, d, J = 8.0Hz).

実施例２５３と同様にして、以下の化合物を得た。
２−（４−フルオロアニリノ）−４−（２−（３−フルオロフェニル）エチル）安息香酸
¹H-NMR(DMSO-d₆)δ値：2.76-2.89(4H,m),6.65(1H,dd,J=8.3,1.5Hz),6.81(1H,d,J=1.2Hz),6.97-7.20(7H,m),7.26-7.34(1H,m),7.80(1H,d,J=8.3Hz).Example 254

In the same manner as in Example 253, the following compound was obtained.
2- (4-Fluoroanilino) -4- (2- (3-fluorophenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.76-2.89 (4H, m), 6.65 (1H, dd, J = 8.3,1.5Hz), 6.81 (1H, d, J = 1.2Hz), 6.97- 7.20 (7H, m), 7.26-7.34 (1H, m), 7.80 (1H, d, J = 8.3Hz).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温でＮ−（４−ヨードフェニル）アセトアミド0.37g、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.41mLおよび酢酸パラジウム5.4mgを加え、130℃で4時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（４−（アセトアミド）フェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（４−（アセトアミド）フェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートに、酢酸2.0mL、ジオキサン2.0mLおよび10％パラジウム−炭素30mgを順次加え、水素雰囲気下、室温で3時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物にトリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の４−（２−（４−（アセトアミド）フェニル）エチル）−２−（４−フルオロアニリノ）安息香酸60mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.02(3H,s),2.77(4H,s),6.65(1H,d,J=8.3Hz),6.71-6.75(1H,m),7.01-7.07(4H,m),7.09-7.16(2H,m),7.47(2H,d,J=8.3Hz),7.79(1H,d,J=8.1Hz),9.48(1H,s),9.87(1H,s),12.89(1H,s).Example 255

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate 0.15 g of N, N-dimethylacetamide in 3.0 mL solution at room temperature with 0.37 g of N- (4-iodophenyl) acetamide, N, N -Dicyclohexylmethylamine 0.41mL and palladium acetate 5.4mg were added, and it stirred at 130 degreeC for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 1: 1], and tert-butyl = 4-((E) -2- (4 -(Acetamido) phenyl) vinyl) -2- (4-fluoroanilino) benzoate was obtained.
To the resulting tert-butyl 4-((E) -2- (4- (acetamido) phenyl) vinyl) -2- (4-fluoroanilino) benzoate, 2.0 mL acetic acid, 2.0 mL dioxane and 10% 30 mg of palladium-carbon was sequentially added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and white solid 4- (2- (4- (acetamido) phenyl) ethyl) -2- (4 -Fluoroanilino) benzoic acid 60 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.02 (3H, s), 2.77 (4H, s), 6.65 (1H, d, J = 8.3 Hz), 6.71-6.75 (1H, m), 7.01- 7.07 (4H, m), 7.09-7.16 (2H, m), 7.47 (2H, d, J = 8.3Hz), 7.79 (1H, d, J = 8.1Hz), 9.48 (1H, s), 9.87 (1H , s), 12.89 (1H, s).

実施例２５５と同様にして、以下の化合物を得た。
２−（４−フルオロアニリノ）−４−（２−（２−（メタンスルホンアミド）フェニル）エチル）安息香酸
¹H-NMR(DMSO-d₆)δ値：2.76-2.82(2H,m),2.91-3.00(5H,m),6.71(1H,d,J=8.3Hz),6.91-6.96(1H,m),7.13-7.26(7H,m),7.29-7.33(1H,m),7.82(1H,d,J=8.0Hz),9.07(1H,s),9.55(1H,s),12.80-13.00(1H,broad).Example 256

In the same manner as in Example 255, the following compound was obtained.
2- (4-Fluoroanilino) -4- (2- (2- (methanesulfonamido) phenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.76-2.82 (2H, m), 2.91-3.00 (5H, m), 6.71 (1H, d, J = 8.3Hz), 6.91-6.96 (1H, m ), 7.13-7.26 (7H, m), 7.29-7.33 (1H, m), 7.82 (1H, d, J = 8.0Hz), 9.07 (1H, s), 9.55 (1H, s), 12.80-13.00 ( 1H, broad).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温でＮ−（３−ブロモフェニル）メタンスルホンアミド0.36g、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.41mLおよび酢酸パラジウム5.4mgを加え、130℃で4時間攪拌した。Ｎ−（３−ブロモフェニル）メタンスルホンアミド0.12g、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.10mLおよび（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）5.4mgを加え、130℃で2時間攪拌した。（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）11mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート6.9mgを加え、130℃で8時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−（メタンスルホンアミド）フェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（３−（メタンスルホンアミド）フェニル）ビニル）ベンゾアートに酢酸2.0mL、ジオキサン2.0mLおよび10％パラジウム−炭素37mgを順次加え、水素雰囲気下、室温で5時間30分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物にトリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の２−（４−フルオロアニリノ）−４−（２−（３−（メタンスルホンアミド）フェニル）エチル）安息香酸75mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.75-2.84(4H,m),2.88(3H,s),6.63-6.68(1H,m),6.75-6.79(1H,m),6.91(1H,d,J=7.8Hz),6.96(1H,s),7.02-7.18(5H,m),7.23(1H,t,J=7.8Hz),7.80(1H,d,J=8.3Hz),9.50(1H,s),9.63(1H,s),12.90(1H,s).Example 257

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate 0.15 g of N, N-dimethylacetamide 3.0 mL solution at room temperature with N- (3-bromophenyl) methanesulfonamide 0.36 g, N , N-dicyclohexylmethylamine 0.41 mL and palladium acetate 5.4 mg were added, and the mixture was stirred at 130 ° C. for 4 hours. N- (3-bromophenyl) methanesulfonamide 0.12 g, N, N-dicyclohexylmethylamine 0.10 mL and (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium ( II) 5.4 mg was added and it stirred at 130 degreeC for 2 hours. Add 11 mg of (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) and 6.9 mg of tri-tert-butylphosphine tetrafluoroborate and add at 130 ° C. for 8 hours. Stir. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 1: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (3- (methanesulfonamido) phenyl) vinyl) benzoate was obtained.
The resulting tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (3- (methanesulfonamido) phenyl) vinyl) benzoate was added with 2.0 mL acetic acid, 2.0 mL dioxane and 10 mL. % Palladium-carbon (37 mg) was sequentially added, and the mixture was stirred at room temperature for 5 hours and 30 minutes in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, the solid was collected by filtration, and white solid 2- (4-fluoroanilino) -4- (2- (3- (methane 75 mg of sulfonamido) phenyl) ethyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.75.2.84 (4H, m), 2.88 (3H, s), 6.63 to 6.68 (1H, m), 6.75 to 6.79 (1H, m), 6.91 (1H , d, J = 7.8Hz), 6.96 (1H, s), 7.02-7.18 (5H, m), 7.23 (1H, t, J = 7.8Hz), 7.80 (1H, d, J = 8.3Hz), 9.50 (1H, s), 9.63 (1H, s), 12.90 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.15gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で４−ブロモ−ｏ−キシレン0.19mL、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.41mLおよび酢酸パラジウム5.4mgを加え、130℃で4時間攪拌した。４−ブロモ−ｏ−キシレン0.063mL、Ｎ，Ｎ−ジシクロヘキシルメチルアミン0.10mLおよび（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）5.4mgを加え、130℃で2時間攪拌した。（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）11mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート6.9mgを加え、130℃で8時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（３，４−ジメチルフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（３，４−ジメチルフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；85-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、４−（（Ｅ）−２−（３，４−ジメチルフェニル）ビニル）−２−（４−フルオロアニリノ）安息香酸を得た。
得られた４−（（Ｅ）−２−（３，４−ジメチルフェニル）ビニル）−２−（４−フルオロアニリノ）安息香酸に、酢酸エチル1.0mL、メタノール1.0mLおよび10％パラジウム−炭素10mgを順次加え、水素雰囲気下、室温で2時間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、白色固体の４−（２−（３，４−ジメチルフェニル）エチル）−２−（４−フルオロアニリノ）安息香酸2.5mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.16(3H,s),2.17(3H,s),2.68-2.81(4H,m),6.66(1H,d,J=8.1Hz),6.80-7.04(4H,m),7.08-7.17(4H,m),7.80(1H,d,J=7.8Hz),9.51(1H,s),12.90(1H,s).Example 258

tert-Butyl-2- (4-fluoroanilino) -4-vinylbenzoate 0.15 g of N, N-dimethylacetamide in 3.0 mL solution, 0.19 mL of 4-bromo-o-xylene at room temperature, N, N-dicyclohexyl 0.41 mL of methylamine and 5.4 mg of palladium acetate were added, and the mixture was stirred at 130 ° C. for 4 hours. 4-Bromo-o-xylene 0.063 mL, N, N-dicyclohexylmethylamine 0.10 mL and (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) 5.4 mg And stirred at 130 ° C. for 2 hours. Add 11 mg of (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) and 6.9 mg of tri-tert-butylphosphine tetrafluoroborate and add at 130 ° C. for 8 hours. Stir. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 4-((E) -2- (3 , 4-Dimethylphenyl) vinyl) -2- (4-fluoroanilino) benzoate.
A solution of tert-butyl = 4-((E) -2- (3,4-dimethylphenyl) vinyl) -2- (4-fluoroanilino) benzoate in trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 85-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 4-((E) -2 -(3,4-Dimethylphenyl) vinyl) -2- (4-fluoroanilino) benzoic acid was obtained.
To the obtained 4-((E) -2- (3,4-dimethylphenyl) vinyl) -2- (4-fluoroanilino) benzoic acid, 1.0 mL of ethyl acetate, 1.0 mL of methanol and 10% palladium-carbon were added. 10 mg was sequentially added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.5 mg of 4- (2- (3,4-dimethylphenyl) ethyl) -2- (4-fluoroanilino) benzoic acid as a white solid. It was.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.16 (3H, s), 2.17 (3H, s), 2.68-2.81 (4H, m), 6.66 (1H, d, J = 8.1 Hz), 6.80- 7.04 (4H, m), 7.08-7.17 (4H, m), 7.80 (1H, d, J = 7.8Hz), 9.51 (1H, s), 12.90 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド3.0mL溶液に、室温で１−ブロモ−４−（トリフルオロメトキシ）ベンゼン0.12g、トリブチルアミン0.15 mLおよび酢酸パラジウム3.6mgを加え、110℃で6時間攪拌した。酢酸パラジウム3.6mgを加え、130℃で6時間攪拌した。１−ブロモ−４−（トリフルオロメトキシ）ベンゼン0.12g、トリブチルアミン0.076mLおよび（Ｅ）−ジ（μ−アセタート）ビス（ｏ−（ジ−ｏ−トリルホスフィノ）ベンジル）ジパラジウム（II）6.3mgを加え、80℃で2時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液、飽和チオ硫酸ナトリウム水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−（トリフルオロメトキシ）フェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−（トリフルオロメトキシ）フェニル）ビニル）ベンゾアートのトリフルオロ酢酸10mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；60-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−（トリフルオロメトキシ）フェニル）ビニル）安息香酸を得た。
得られた２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（４−（トリフルオロメトキシ）フェニル）ビニル）安息香酸に、酢酸エチル1.0mL、メタノール1.0mLおよび10％パラジウム−炭素2.0mgを順次加え、水素雰囲気下、室温で2時間30分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去し、白色固体の２−（４−フルオロアニリノ）−４−（２−（４−（トリフルオロメトキシ）フェニル）エチル）安息香酸3.4mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.74-2.82(2H,m),2.84-2.93(2H,m),6.52(1H,d,J=8.0Hz),6.83(1H,s),6.95-7.08(4H,m),7.25(2H,d,J=8.7Hz),7.31(2H,d,J=8.7Hz),7.80(1H,d,J=7.8Hz).Example 259

To a solution of tert-butyl 2- (4-fluoroanilino) -4-vinylbenzoate (0.10 g) in N, N-dimethylacetamide (3.0 mL) at room temperature is 0.12 g of 1-bromo-4- (trifluoromethoxy) benzene, Tributylamine 0.15 mL and palladium acetate 3.6 mg were added, and the mixture was stirred at 110 ° C. for 6 hours. 3.6 mg of palladium acetate was added and stirred at 130 ° C. for 6 hours. 1-Bromo-4- (trifluoromethoxy) benzene 0.12 g, tributylamine 0.076 mL and (E) -di (μ-acetate) bis (o- (di-o-tolylphosphino) benzyl) dipalladium (II) 6.3 mg And stirred at 80 ° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (4- (trifluoromethoxy) phenyl) vinyl) benzoate was obtained.
A solution of the resulting tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (4- (trifluoromethoxy) phenyl) vinyl) benzoate in 10 mL of trifluoroacetic acid was added at room temperature to 2 mL. Stir for hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 60-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2- (4-fluoroanilino). ) -4-((E) -2- (4- (trifluoromethoxy) phenyl) vinyl) benzoic acid was obtained.
To the obtained 2- (4-fluoroanilino) -4-((E) -2- (4- (trifluoromethoxy) phenyl) vinyl) benzoic acid, 1.0 mL of ethyl acetate, 1.0 mL of methanol and 10% palladium were added. -Carbon 2.0mg was added in order, and it stirred under hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and white solid 2- (4-fluoroanilino) -4- (2- (4- (trifluoromethoxy) phenyl) ethyl) benzoic acid 3.4 mg Got.
¹ H-NMR (DMSO-d ₆ ) δ values: 2.74.2.82 (2H, m), 2.84.93 (2H, m), 6.52 (1H, d, J = 8.0 Hz), 6.83 (1H, s), 6.95-7.08 (4H, m), 7.25 (2H, d, J = 8.7Hz), 7.31 (2H, d, J = 8.7Hz), 7.80 (1H, d, J = 7.8Hz).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド2.0mL溶液に、室温で３−ブロモ−ｏ−キシレン0.064mL、トリブチルアミン0.15mL、酢酸パラジウム4.0mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート3.0mgを加え、窒素雰囲気下、120℃で2時間攪拌した。酢酸パラジウム4.0mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート3.0mgを加え、窒素雰囲気下、120℃で2時間攪拌した。３−ブロモ−ｏ−キシレン0.064mL、トリブチルアミン0.11mL、酢酸パラジウム4.0mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート3.0mgを加え、窒素雰囲気下、120℃で5時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２，３−ジメチルフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（２，３−ジメチルフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートに、酢酸エチル1.5mL、メタノール1.5mLおよび10％パラジウム−炭素27mgを順次加え、水素雰囲気下、室温で3時間20分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物に、塩化メチレン1.0mLおよびトリフルオロ酢酸7.5mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の４−（２−（２，３−ジメチルフェニル）エチル）−２−（４−フルオロアニリノ）安息香酸17mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.09(3H,s),2.22(3H,s),2.70(2H,t,J=7.5Hz),2.83(2H,t,J=7.5Hz),6.68(1H,d,J=8.3Hz),6.77(1H,s),6.87-6.92(1H,m),6.96(1H,t,J=7.3Hz),7.01(1H,d,J=7.3Hz),7.07-7.15(4H,m),7.81(1H,d,J=8.0Hz),9.47-9.57(1H,broad),12.85-12.96(1H,broad).Example 260

tert-Butyl 2- (4-fluoroanilino) -4-vinylbenzoate In a solution of 0.10 g of N, N-dimethylacetamide in 2.0 mL at room temperature was 0.064 mL of 3-bromo-o-xylene, 0.15 mL of tributylamine, Palladium acetate (4.0 mg) and tri-tert-butylphosphine tetrafluoroborate (3.0 mg) were added, and the mixture was stirred at 120 ° C. for 2 hours under a nitrogen atmosphere. Palladium acetate (4.0 mg) and tri-tert-butylphosphine tetrafluoroborate (3.0 mg) were added, and the mixture was stirred at 120 ° C. for 2 hours under a nitrogen atmosphere. 0.064 mL of 3-bromo-o-xylene, 0.11 mL of tributylamine, 4.0 mg of palladium acetate and 3.0 mg of tri-tert-butylphosphine tetrafluoroborate were added, and the mixture was stirred at 120 ° C. for 5 hours in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 10: 1], and tert-butyl = 4-((E) -2 -(2,3-Dimethylphenyl) vinyl) -2- (4-fluoroanilino) benzoate was obtained.
The resulting tert-butyl 4-((E) -2- (2,3-dimethylphenyl) vinyl) -2- (4-fluoroanilino) benzoate was added to 1.5 mL of ethyl acetate, 1.5 mL of methanol and 10 mL. % Palladium-carbon (27 mg) was sequentially added, and the mixture was stirred at room temperature for 3 hours and 20 minutes in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, methylene chloride (1.0 mL) and trifluoroacetic acid (7.5 mL) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and white solid 4- (2- (2,3-dimethylphenyl) ethyl) -2- (4 -Fluoroanilino) benzoic acid 17 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.09 (3H, s), 2.22 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 2.83 (2H, t, J = 7.5 Hz) , 6.68 (1H, d, J = 8.3Hz), 6.77 (1H, s), 6.87-6.92 (1H, m), 6.96 (1H, t, J = 7.3Hz), 7.01 (1H, d, J = 7.3) Hz), 7.07-7.15 (4H, m), 7.81 (1H, d, J = 8.0Hz), 9.47-9.57 (1H, broad), 12.85-12.96 (1H, broad).

Examples 261-262
In the same manner as in Example 260, the compounds shown in Table 34 were obtained.

2- (4-Fluoroanilino) -4- (2- (3- (trifluoromethoxy) phenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.92 (4H, m), 6.66 (1H, d, J = 8.0 Hz), 6.80 (1H, s), 7.07-7.23 (7H, m), 7.40 (1H, t, J = 7.9Hz), 7.80 (1H, d, J = 8.1Hz), 9.47-9.55 (1H, broad), 12.85-12.96 (1H, broad).

4- (2- (3-acetamidophenyl) ethyl) -2- (4-fluoroanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.01 (3H, s), 2.78 (4H, s), 6.66 (1H, d, J = 8.3 Hz), 6.75 (1H, s), 6.81 (1H, d, J = 7.8Hz), 7.04-7.20 (5H, m), 7.36 (1H, s), 7.45 (1H, d, J = 8.0Hz), 7.80 (1H, d, J = 8.3Hz), 9.50 ( 1H, s), 9.85 (1H, s), 12.84-12.94 (1H, broad).

ｔｅｒｔ−ブチル＝４−ブロモ−２−（４−フルオロアニリノ）ベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド2.0mL溶液に、室温で３，４−ジメトキシスチレン0.081mL、トリブチルアミン0.13mL、酢酸パラジウム3.0mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート2.0mgを加え、窒素雰囲気下、120℃で2時間攪拌した。酢酸パラジウム3.0mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート2.0mgを加え、120℃で2時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（３，４−ジメトキシフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（（Ｅ）−２−（３，４−ジメトキシフェニル）ビニル）−２−（４−フルオロアニリノ）ベンゾアートに、酢酸エチル1.5mL、メタノール1.5mLおよび10％パラジウム−炭素28mgを順次加え、水素雰囲気下、室温で3時間30分間攪拌した。不溶物をろ去後、減圧下で溶媒を留去した。得られた残留物にトリフルオロ酢酸7.5mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の４−（２−（３，４−ジメトキシフェニル）エチル）−２−（４−フルオロアニリノ）安息香酸56mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.73-2.81(4H,m),3.68(3H,s),3.71(3H,s),6.61(1H,dd,J=8.0,2.0Hz),6.67(1H,dd,J=8.0,1.2Hz),6.77(2H,s),6.82(1H,d,J=8.3Hz),7.02-7.15(4H,m),7.80(1H,d,J=8.0Hz),9.49(1H,s),12.89(1H,s).Example 263

tert-butyl 4-bromo-2- (4-fluoroanilino) benzoate (0.10 g) in N, N-dimethylacetamide (2.0 mL) at room temperature, 0.04 mL of 3,4-dimethoxystyrene, 0.13 mL of tributylamine, acetic acid Palladium 3.0 mg and tri-tert-butylphosphine tetrafluoroborate 2.0 mg were added, and the mixture was stirred at 120 ° C. for 2 hours under a nitrogen atmosphere. Palladium acetate (3.0 mg) and tri-tert-butylphosphine tetrafluoroborate (2.0 mg) were added, and the mixture was stirred at 120 ° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 4-((E) -2- (3 , 4-Dimethoxyphenyl) vinyl) -2- (4-fluoroanilino) benzoate.
The resulting tert-butyl 4-((E) -2- (3,4-dimethoxyphenyl) vinyl) -2- (4-fluoroanilino) benzoate was added with 1.5 mL of ethyl acetate, 1.5 mL of methanol and 10 mL. % Palladium-carbon 28 mg was sequentially added, and the mixture was stirred at room temperature for 3 hours 30 minutes in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. To the obtained residue, 7.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 4- (2- (3,4-dimethoxyphenyl) ethyl) -2- (4 -Fluoroanilino) benzoic acid 56 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.73-2.81 (4H, m), 3.68 (3H, s), 3.71 (3H, s), 6.61 (1H, dd, J = 8.0, 2.0 Hz), 6.67 (1H, dd, J = 8.0,1.2Hz), 6.77 (2H, s), 6.82 (1H, d, J = 8.3Hz), 7.02-7.15 (4H, m), 7.80 (1H, d, J = 8.0Hz), 9.49 (1H, s), 12.89 (1H, s).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−ビニルベンゾアート0.10gのＮ，Ｎ−ジメチルアセトアミド2.0mL溶液に、室温で２−ヨードアニソール0.046mL、トリブチルアミン0.15mL、酢酸パラジウム4.0mgおよびトリ−ｔｅｒｔ−ブチルホスフィンテトラフルオロボラート3.0mgを加え、窒素雰囲気下、110℃で1時間30分間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、10％クエン酸水溶液および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２０：１］で精製し、ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（２−メトキシフェニル）ビニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（（Ｅ）−２−（２−メトキシフェニル）ビニル）ベンゾアートに、酢酸4.0mLおよび10％パラジウム−炭素26mgを順次加え、水素雰囲気下、室温で7時間攪拌した。次いで、10％パラジウム−炭素39mgを加え、水素雰囲気下、同温度で3時間攪拌後、40℃で2時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、10％パラジウム−炭素64mgを加え、水素雰囲気下、40℃で3時間30分間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、減圧下で溶媒を留去した。得られた残留物に、水、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去し、淡赤色油状物のｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−（２−メトキシフェニル）エチル）ベンゾアート0.11gを得た。
¹H-NMR(DMSO-d₆)δ値：1.55(9H,s),2.69-2.82(4H,m),3.73(3H,s),6.64(1H,dd,J=8.3,1.2Hz),6.75(1H,s),6.81(1H,t,J=7.4Hz),6.94-7.00(2H,m),7.05-7.23(5H,m),7.75(1H,d,J=8.3Hz),9.25(1H,s).Example 264

tert-Butyl-2- (4-fluoroanilino) -4-vinylbenzoate In a solution of 0.10 g of N, N-dimethylacetamide in 2.0 mL, 0.046 mL of 2-iodoanisole, 0.15 mL of tributylamine, 4.0 of palladium acetate at room temperature mg and 3.0 mg of tri-tert-butylphosphine tetrafluoroborate were added, and the mixture was stirred at 110 ° C. for 1 hour and 30 minutes under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed successively with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 20: 1], and tert-butyl = 2- (4-fluoroanilino) -4. -((E) -2- (2-methoxyphenyl) vinyl) benzoate was obtained.
To the obtained tert-butyl = 2- (4-fluoroanilino) -4-((E) -2- (2-methoxyphenyl) vinyl) benzoate, 4.0 mL of acetic acid and 26 mg of 10% palladium-carbon were sequentially added. In addition, the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. Next, 39 mg of 10% palladium-carbon was added, and the mixture was stirred at the same temperature for 3 hours in a hydrogen atmosphere, and then stirred at 40 ° C. for 2 hours. The reaction mixture was cooled to room temperature, insolubles were filtered off, 10% palladium-carbon (64 mg) was added, and the mixture was stirred at 40 ° C. for 3 hr 30 min in a hydrogen atmosphere. The reaction mixture was cooled to room temperature, insoluble material was filtered off, and the solvent was distilled off under reduced pressure. Water, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and tert-butyl 2- (4-fluoroanilino)- 0.11 g of 4- (2- (2-methoxyphenyl) ethyl) benzoate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 1.55 (9H, s), 2.69-2.82 (4H, m), 3.73 (3H, s), 6.64 (1H, dd, J = 8.3, 1.2 Hz), 6.75 (1H, s), 6.81 (1H, t, J = 7.4Hz), 6.94-7.00 (2H, m), 7.05-7.23 (5H, m), 7.75 (1H, d, J = 8.3Hz), 9.25 (1H, s).

実施例２６４と同様にして、以下の化合物を得た。
ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−（４−（メタンスルホンアミド）フェニル）エチル）ベンゾアート
¹H-NMR(DMSO-d₆)δ値：1.55(9H,s),2.78(4H,s),2.92(3H,s),6.66(1H,dd,J=8.3,1.5Hz),6.77(1H,d,J=1.5Hz),7.05-7.18(8H,m),7.75(1H,d,J=8.0Hz),9.25(1H,s),9.60-9.70(1H,broad).Example 265

In the same manner as in Example 264, the following compound was obtained.
tert-butyl = 2- (4-fluoroanilino) -4- (2- (4- (methanesulfonamido) phenyl) ethyl) benzoate
¹ H-NMR (DMSO-d ₆ ) δ value: 1.55 (9H, s), 2.78 (4H, s), 2.92 (3H, s), 6.66 (1H, dd, J = 8.3, 1.5 Hz), 6.77 ( 1H, d, J = 1.5Hz), 7.05-7.18 (8H, m), 7.75 (1H, d, J = 8.0Hz), 9.25 (1H, s), 9.60-9.70 (1H, broad).

ｔｅｒｔ−ブチル＝２−（４−フルオロアニリノ）−４−（２−（２−メトキシフェニル）エチル）ベンゾアート0.11gのトリフルオロ酢酸7.5mL溶液を室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の２−（４−フルオロアニリノ）−４−（２−（２−メトキシフェニル）エチル）安息香酸12mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.70-2.82(4H,m),3.73(3H,s),6.64(1H,dd,J=8.3,1.3Hz),6.76(1H,s),6.82(1H,td,J=7.4,0.9Hz),6.96(1H,d,J=8.3Hz),7.00(1H,dd,J=7.3,1.7Hz),7.07-7.23(5H,m),7.80(1H,d,J=8.3Hz),9.51(1H,s),12.82-12.93(1H,broad).Example 266

A solution of 0.11 g of tert-butyl = 2- (4-fluoroanilino) -4- (2- (2-methoxyphenyl) ethyl) benzoate in 7.5 mL of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and white solid 2- (4-fluoroanilino) -4- (2- (2-methoxyphenyl) was collected. ) Ethyl) 12 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.70-2.82 (4H, m), 3.73 (3H, s), 6.64 (1H, dd, J = 8.3, 1.3 Hz), 6.76 (1H, s), 6.82 (1H, td, J = 7.4,0.9Hz), 6.96 (1H, d, J = 8.3Hz), 7.00 (1H, dd, J = 7.3,1.7Hz), 7.07-7.23 (5H, m), 7.80 (1H, d, J = 8.3Hz), 9.51 (1H, s), 12.82-12.93 (1H, broad).

実施例２６６と同様にして、以下の化合物を得た。
２−(４−フルオロアニリノ）−４−（２−（４−（メタンスルホンアミド）フェニル）エチル）安息香酸
¹H-NMR(DMSO-d₆)δ値：2.78(4H,s),2.92(3H,s),6.66(1H,dd,J=8.2,1.2Hz),6.78(1H,s),7.05-7.19(8H,m),7.80(1H,d,J=8.2Hz),9.40-9.60(1H,broad),9.62(1H,s),12.70-13.00(1H,broad).Example 267

In the same manner as in Example 266, the following compound was obtained.
2- (4-Fluoroanilino) -4- (2- (4- (methanesulfonamido) phenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78 (4H, s), 2.92 (3H, s), 6.66 (1H, dd, J = 8.2, 1.2 Hz), 6.78 (1H, s), 7.05- 7.19 (8H, m), 7.80 (1H, d, J = 8.2Hz), 9.40-9.60 (1H, broad), 9.62 (1H, s), 12.70-13.00 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−（３−クロロフェニル）ベンゾアート0.12gおよび炭酸セシウム0.32gのトルエン3.0mL懸濁液に、室温で１−ヨード−３，４−メチレンジオキシベンゼン0.20g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.6mgおよび酢酸パラジウム1.8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.6mgおよび酢酸パラジウム1.8mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（３−クロロフェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（３−クロロフェニル）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（３−クロロフェニル）安息香酸52mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.04(2H,s),6.79(1H,dd,J=8.2,2.1Hz),6.93(1H,d,J=8.2Hz),6.98(1H,d,J=2.1Hz),7.01(1H,dd,J=8.3,1.7Hz),7.14-7.19(1H,m),7.43-7.53(3H,m),7.60(1H,s),7.95(1H,d,J=8.3Hz),9.51(1H,s),13.00-13.15(1H,broad).Example 268

To a suspension of 0.12 g of tert-butyl-2-amino-4- (3-chlorophenyl) benzoate and 0.32 g of cesium carbonate in 3.0 mL of toluene was added 0.20 g of 1-iodo-3,4-methylenedioxybenzene at room temperature, 9.4 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.6 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.8 mg of palladium acetate were added, and the mixture was stirred at 110 ° C. for 24 hours. After the reaction mixture was cooled to room temperature, 9.4 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.6 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.8 mg of palladium acetate were added. The mixture was stirred at 110 ° C. for 21 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((benzo-1,3-dioxole). -5-yl) amino) -4- (3-chlorophenyl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzo-1,3-dioxol-5-yl) amino) -4- (3-chlorophenyl) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. did. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give 2-((benzo-1,3-dioxol-5-yl) amino) -4 as a yellow solid. -(3-Chlorophenyl) benzoic acid 52 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.04 (2H, s), 6.79 (1H, dd, J = 8.2, 2.1 Hz), 6.93 (1H, d, J = 8.2 Hz), 6.98 (1H, d, J = 2.1Hz), 7.01 (1H, dd, J = 8.3,1.7Hz), 7.14-7.19 (1H, m), 7.43-7.53 (3H, m), 7.60 (1H, s), 7.95 (1H , d, J = 8.3Hz), 9.51 (1H, s), 13.00-13.15 (1H, broad).

Examples 269, 270
In the same manner as in Example 268, the compounds shown in Table 35 were obtained.

2-anilino-4- (3-chlorophenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.06-7.14 (2H, m), 7.30-7.58 (8H, m), 7.64 (1H, s), 7.99 (1H, d, J = 8.3 Hz), 9.71 (1H, s), 13.10-13.30 (1H, broad).

4- (3-Chlorophenyl) -2- (2-methylanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.24 (3H, s), 7.01-7.13 (3H, m), 7.22-7.29 (1H, m), 7.33 (1H, d, J = 7.3 Hz), 7.40-7.51 (4H, m), 7.57 (1H, d, J = 1.5Hz), 7.99 (1H, d, J = 8.3Hz), 9.60 (1H, s), 13.05-13.25 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−（３−クロロフェニル）ベンゾアート0.12gおよび炭酸セシウム0.32gのトルエン3.0mL懸濁液に、室温で３−ヨードフェノール0.17g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.6mgおよび酢酸パラジウム1.8mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.6mgおよび酢酸パラジウム1.8mgを加え、110℃で21時間攪拌した。炭酸セシウム64mg、３−ヨードフェノール43mg、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.6mgおよび酢酸パラジウム1.8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝５：１］で精製し、ｔｅｒｔ−ブチル＝４−（３−クロロフェニル）−２−（（３−ヒドロキシフェニル）アミノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（３−クロロフェニル）−２−（（３−ヒドロキシフェニル）アミノ）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；80-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の４−（３−クロロフェニル）−２−（（３−ヒドロキシフェニル）アミノ）安息香酸22mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.46-6.52(1H,m),6.69-6.76(2H,m),7.08(1H,dd,J=8.3,1.5Hz),7.16(1H,t,J=7.9Hz),7.44-7.53(3H,m),7.54-7.60(1H,m),7.65(1H,s),7.98(1H,d,J=8.3Hz),9.49(1H,s),9.66(1H,s),13.05-13.30(1H,broad).Example 271

To a suspension of 0.12 g of tert-butyl = 2-amino-4- (3-chlorophenyl) benzoate and 0.32 g of cesium carbonate in 3.0 mL of toluene was added 0.17 g of 3-iodophenol, 2-dicyclohexylphosphino-2 ′ at room temperature. , 4 ′, 6′-triisopropylbiphenyl 9.4 mg, tris (dibenzylideneacetone) dipalladium (0) 3.6 mg and palladium acetate 1.8 mg were added, and the mixture was stirred at 110 ° C. for 24 hours. 9.4 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.6 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.8 mg of palladium acetate were added, and the mixture was stirred at 110 ° C. for 21 hours. Cesium carbonate 64 mg, 3-iodophenol 43 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.4 mg, tris (dibenzylideneacetone) dipalladium (0) 3.6 mg and palladium acetate 1.8 mg The mixture was further stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 5: 1], and tert-butyl = 4- (3-chlorophenyl) -2- ( (3-Hydroxyphenyl) amino) benzoate was obtained.
To the obtained tert-butyl = 4- (3-chlorophenyl) -2-((3-hydroxyphenyl) amino) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 80-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 4- (3- Chlorophenyl) -2-((3-hydroxyphenyl) amino) benzoic acid 22 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.46-6.52 (1H, m), 6.69-6.76 (2H, m), 7.08 (1H, dd, J = 8.3,1.5 Hz), 7.16 (1H, t , J = 7.9Hz), 7.44-7.53 (3H, m), 7.54-7.60 (1H, m), 7.65 (1H, s), 7.98 (1H, d, J = 8.3Hz), 9.49 (1H, s) , 9.66 (1H, s), 13.05-13.30 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−（３−クロロフェニル）ベンゾアート0.12gおよび炭酸セシウム0.32gのトルエン3.0mL懸濁液に、室温で５−ブロモベンゾチオフェン0.17g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.6mgおよび酢酸パラジウム1.8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.6mgおよび酢酸パラジウム1.8mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（３−クロロフェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（３−クロロフェニル）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；80-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の２−（（ベンゾチオフェン−５−イル）アミノ）−４−（３−クロロフェニル）安息香酸10mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.08(1H,dd,J=8.3,1.7Hz),7.37(1H,dd,J=8.5,2.1Hz),7.37-7.56(5H,m),7.63(1H,s),7.78(1H,d,J=5.4Hz),7.86(1H,d,J=2.1Hz),8.00(2H,d,J=8.3Hz),9.79(1H,s),13.10-13.25(1H,broad).Example 272

To a suspension of 0.12 g of tert-butyl-2-amino-4- (3-chlorophenyl) benzoate and 0.32 g of cesium carbonate in 3.0 mL of toluene was added 0.17 g of 5-bromobenzothiophene, 2-dicyclohexylphosphino-2 at room temperature. 9.4 mg of ', 4', 6'-triisopropylbiphenyl, 3.6 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.8 mg of palladium acetate were added and stirred at 110 ° C. for 24 hours. After the reaction mixture was cooled to room temperature, 9.4 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.6 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.8 mg of palladium acetate were added. The mixture was stirred at 110 ° C. for 21 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((benzothiophen-5-yl). Amino) -4- (3-chlorophenyl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzothiophen-5-yl) amino) -4- (3-chlorophenyl) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 80-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((benzo 10 mg of thiophen-5-yl) amino) -4- (3-chlorophenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.08 (1H, dd, J = 8.3, 1.7 Hz), 7.37 (1H, dd, J = 8.5, 2.1 Hz), 7.37-7.56 (5H, m), 7.63 (1H, s), 7.78 (1H, d, J = 5.4Hz), 7.86 (1H, d, J = 2.1Hz), 8.00 (2H, d, J = 8.3Hz), 9.79 (1H, s), 13.10-13.25 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−（４−（メタンスルホンアミド）フェニル）ベンゾアート0.12gおよび炭酸セシウム0.27gのトルエン3.0mL懸濁液に、室温で２−ヨードトルエン0.084mL、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.9mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび酢酸パラジウム1.5mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.9mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび酢酸パラジウム1.5mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、ｔｅｒｔ−ブチル＝４−（４−（メタンスルホンアミド）フェニル）−２−（２−メチルアニリノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（４−（メタンスルホンアミド）フェニル）−２−（２−メチルアニリノ）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の４−（４−（メタンスルホンアミド）フェニル）−２−（２−メチルアニリノ）安息香酸52mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.24(3H,s),3.01(3H,s),7.00(1H,dd,J=8.3,1.7Hz),7.04-7.12(2H,m),7.22-7.29(3H,m),7.33(1H,d,J=7.0Hz),7.39-7.44(1H,m),7.48-7.54(2H,m),7.96(1H,d,J=8.3Hz),9.59(1H,s),9.90(1H,s),12.95-13.15(1H,broad).Example 273

To a suspension of tert-butyl 2-amino-4- (4- (methanesulfonamido) phenyl) benzoate 0.12 g and cesium carbonate 0.27 g in toluene 3.0 mL, 2-iodotoluene 0.084 mL, 2-dicyclohexyl at room temperature Phosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.9 mg), tris (dibenzylideneacetone) dipalladium (0) (3.0 mg) and palladium acetate (1.5 mg) were added, and the mixture was stirred at 110 ° C. for 24 hours. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.9 mg), tris (dibenzylideneacetone) dipalladium (0) (3.0 mg) and palladium acetate (1.5 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 2: 1], and tert-butyl = 4- (4- (methanesulfonamido) phenyl. ) -2- (2-Methylanilino) benzoate was obtained.
To the obtained tert-butyl = 4- (4- (methanesulfonamido) phenyl) -2- (2-methylanilino) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to give 4- (4- (methanesulfonamido) phenyl) -2- (2-methylanilino) as a yellow solid. 52 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.24 (3H, s), 3.01 (3H, s), 7.00 (1H, dd, J = 8.3, 1.7 Hz), 7.04-7.12 (2H, m), 7.22-7.29 (3H, m), 7.33 (1H, d, J = 7.0Hz), 7.39-7.44 (1H, m), 7.48-7.54 (2H, m), 7.96 (1H, d, J = 8.3Hz) , 9.59 (1H, s), 9.90 (1H, s), 12.95-13.15 (1H, broad).

実施例２７３と同様にして、以下の化合物を得た。
２−アニリノ−４−（４−（メタンスルホンアミド）フェニル）安息香酸
¹H-NMR(DMSO-d₆)δ値：3.02(3H,s),7.05(1H,dd,J=8.3,1.7Hz),7.06-7.13(1H,m),7.25-7.43(7H,m),7.54-7.61(2H,m),7.97(1H,d,J=8.3Hz),9.71(1H,s),9.92(1H,s),13.00-13.20(1H,broad).Example 274

In the same manner as in Example 273, the following compound was obtained.
2-anilino-4- (4- (methanesulfonamido) phenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.02 (3H, s), 7.05 (1H, dd, J = 8.3, 1.7 Hz), 7.06-7.13 (1H, m), 7.25-7.43 (7H, m ), 7.54-7.61 (2H, m), 7.97 (1H, d, J = 8.3Hz), 9.71 (1H, s), 9.92 (1H, s), 13.00-13.20 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−（４−（メタンスルホンアミド）フェニル）ベンゾアート0.12gおよび炭酸セシウム0.27gのトルエン3.0mL懸濁液に、室温で１−ヨード−３，４−メチレンジオキシベンゼン0.16g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.9mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび酢酸パラジウム1.5mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.9mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび酢酸パラジウム1.5mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（４−（メタンスルホンアミド）フェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（４−（メタンスルホンアミド）フェニル）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-90％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（４−（メタンスルホンアミド）フェニル）安息香酸2.8mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.02(3H,s),6.04(2H,s),6.74-6.83(1H,m),6.90-7.01(3H,m),7.13-7.18(1H,m),7.24-7.31(2H,m),7.50-7.57(2H,m),7.93(1H,d,J=8.3Hz),9.51(1H,s),9.91(1H,s).Example 275

To a suspension of 0.12 g of tert-butyl = 2-amino-4- (4- (methanesulfonamido) phenyl) benzoate and 0.27 g of cesium carbonate in 3.0 mL of toluene was added 1-iodo-3,4-methylenedi at room temperature. Add 0.16 g of oxybenzene, 7.9 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.0 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.5 mg of palladium acetate at 110 ° C. Stir for 24 hours. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.9 mg), tris (dibenzylideneacetone) dipalladium (0) (3.0 mg) and palladium acetate (1.5 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 2: 1], and tert-butyl = 2-((benzo-1,3-dioxole). -5-yl) amino) -4- (4- (methanesulfonamido) phenyl) benzoate was obtained.
To the resulting tert-butyl = 2-((benzo-1,3-dioxol-5-yl) amino) -4- (4- (methanesulfonamido) phenyl) benzoate was added 5.0 mL of trifluoroacetic acid, Stir at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 50-90% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((benzo 2.8 mg of -1,3-dioxol-5-yl) amino) -4- (4- (methanesulfonamido) phenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.02 (3H, s), 6.04 (2H, s), 6.74-6.83 (1H, m), 6.90-7.01 (3H, m), 7.13-7.18 (1H , m), 7.24-7.31 (2H, m), 7.50-7.57 (2H, m), 7.93 (1H, d, J = 8.3Hz), 9.51 (1H, s), 9.91 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（４−（メタンスルホンアミド）フェニル）ベンゾアート0.12gおよび炭酸セシウム0.27gのトルエン3.0mL懸濁液に、室温で５−ブロモベンゾチオフェン0.14g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.9mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.0mgおよび酢酸パラジウム1.5mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（４−（メタンスルホンアミド）フェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（４−（メタンスルホンアミド）フェニル）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（（ベンゾチオフェン−５−イル）アミノ）−４−（４−（メタンスルホンアミド）フェニル）安息香酸52mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.01(3H,s),7.04(1H,dd,J=8.3,1.5Hz),7.26(2H,d,J=8.6Hz),7.36(1H,dd,J=8.6,2.1Hz),7.36-7.41(1H,m),7.44(1H,d,J=5.4Hz),7.56(2H,d,J=8.6Hz),7.78(1H,d,J=5.4Hz),7.84(1H,d,J=2.1Hz),7.95-8.02(2H,m),9.78(1H,s),9.90(1H,s),13.00-13.15(1H,broad).Example 276

To a suspension of 0.12 g of tert-butyl = 2-amino-4- (4- (methanesulfonamido) phenyl) benzoate and 0.27 g of cesium carbonate in 3.0 mL of toluene was added 0.14 g of 5-bromobenzothiophene, 2- Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.9 mg), tris (dibenzylideneacetone) dipalladium (0) (3.0 mg) and palladium acetate (1.5 mg) were added, and the mixture was stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 2: 1], and tert-butyl = 2-((benzothiophen-5-yl). Amino) -4- (4- (methanesulfonamido) phenyl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzothiophen-5-yl) amino) -4- (4- (methanesulfonamido) phenyl) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. did. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 2-((benzothiophen-5-yl) amino) -4- (4- (4- ( 52 mg of methanesulfonamido) phenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.01 (3H, s), 7.04 (1H, dd, J = 8.3, 1.5 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 8.6,2.1Hz), 7.36-7.41 (1H, m), 7.44 (1H, d, J = 5.4Hz), 7.56 (2H, d, J = 8.6Hz), 7.78 (1H, d, J = 5.4Hz), 7.84 (1H, d, J = 2.1Hz), 7.95-8.02 (2H, m), 9.78 (1H, s), 9.90 (1H, s), 13.00-13.15 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.12gおよび炭酸セシウム0.33gのトルエン3.0mL懸濁液に、室温で２−ブロモ−Ｎ，Ｎ−ジメチルアニリン0.16g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mgおよび酢酸パラジウム1.8mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mgおよび酢酸パラジウム1.8mgを加え、110℃で21時間攪拌した。炭酸セシウム66mg、２−ブロモ−Ｎ，Ｎ−ジメチルアニリン40mg、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mgおよび酢酸パラジウム1.8mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（２−（ジメチルアミノ）フェニル）アミノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（２−（ジメチルアミノ）フェニル）アミノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-85％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、酢酸エチル、水および飽和炭酸水素ナトリウム水溶液を加えてpH6.5に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、黄色固体の２−（（２−（ジメチルアミノ）フェニル）アミノ）−４−フェネチル安息香酸7.0mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.59(6H,s),2.78-2.90(4H,m),6.67(1H,dd,J=8.1,1.2Hz),6.89-7.12(5H,m),7.13-7.30(5H,m),7.80(1H,d,J=8.1Hz),9.56(1H,s),12.73(1H,s).Example 277

To a suspension of 0.12 g of tert-butyl = 2-amino-4-phenethylbenzoate and 0.33 g of cesium carbonate in 3.0 mL of toluene was added 0.16 g of 2-bromo-N, N-dimethylaniline at room temperature, 2-dicyclohexylphosphino- 9.6 mg of 2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.8 mg of palladium acetate were added, and the mixture was stirred at 110 ° C. for 24 hours. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (9.6 mg), tris (dibenzylideneacetone) dipalladium (0) (3.7 mg) and palladium acetate (1.8 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. Cesium carbonate 66 mg, 2-bromo-N, N-dimethylaniline 40 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.6 mg, tris (dibenzylideneacetone) dipalladium (0) 3.7 mg Then, 1.8 mg of palladium acetate was added, and the mixture was stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((2- (dimethylamino) phenyl ) Amino) -4-phenethylbenzoate was obtained.
To the obtained tert-butyl = 2-((2- (dimethylamino) phenyl) amino) -4-phenethylbenzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 50-85% acetonitrile / 0.1% aqueous trifluoroacetic acid solution], and then ethyl acetate, water and saturated bicarbonate A sodium aqueous solution was added to adjust the pH to 6.5. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the resulting residue, and the solid was collected by filtration to obtain 7.0 mg of 2-((2- (dimethylamino) phenyl) amino) -4-phenethylbenzoic acid as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.59 (6H, s), 2.78-2.90 (4H, m), 6.67 (1H, dd, J = 8.1, 1.2 Hz), 6.89-7.12 (5H, m ), 7.13-7.30 (5H, m), 7.80 (1H, d, J = 8.1Hz), 9.56 (1H, s), 12.73 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（３−（ｔｅｒｔ−ブトキシカルボニルオキシ）フェニル）ベンゾアート0.12gおよび炭酸セシウム0.25gのトルエン3.0mL懸濁液に、室温で３−ヨードフェノール0.14g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）2.9mgおよび酢酸パラジウム1.4mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）2.9mgおよび酢酸パラジウム1.4mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝３：１］で精製し、ｔｅｒｔ−ブチル＝４−（３−（ｔｅｒｔ−ブトキシカルボニル）オキシフェニル）−２−（（３−ヒドロキシフェニル）アミノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（３−（ｔｅｒｔ−ブトキシカルボニル）オキシフェニル）−２−（（３−ヒドロキシフェニル）アミノ）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物にヘキサンおよびジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の４−（３−ヒドロキシフェニル）−２−（（３−ヒドロキシフェニル）アミノ）安息香酸10mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.50(1H,d,J=7.6Hz),6.68-6.74(2H,m),6.76-6.82(1H,m),6.92-7.06(3H,m),7.12-7.20(1H,m),7.22-7.29(1H,m),7.39-7.44(1H,m),7.95(1H,d,J=8.3Hz),9.49(1H,s),9.58(1H,s),9.62(1H,s),13.08(1H,s).Example 278

tert-Butyl-2-amino-4- (3- (tert-butoxycarbonyloxy) phenyl) benzoate 0.12 g and cesium carbonate 0.25 g in a toluene 3.0 mL suspension at room temperature with 0.14 g of 3-iodophenol, 2 -Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.4 mg), tris (dibenzylideneacetone) dipalladium (0) (2.9 mg) and palladium acetate (1.4 mg) were added, and the mixture was stirred at 110 ° C. for 24 hours. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.4 mg), tris (dibenzylideneacetone) dipalladium (0) (2.9 mg) and palladium acetate (1.4 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 3: 1], and tert-butyl = 4- (3- (tert-butoxycarbonyl). Oxyphenyl) -2-((3-hydroxyphenyl) amino) benzoate was obtained.
To the obtained tert-butyl = 4- (3- (tert-butoxycarbonyl) oxyphenyl) -2-((3-hydroxyphenyl) amino) benzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. did. The solvent was distilled off under reduced pressure, hexane and diisopropyl ether were added to the obtained residue, and the solid was collected by filtration to give 4- (3-hydroxyphenyl) -2-((3-hydroxyphenyl) as a yellow solid. 10 mg of amino) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.50 (1H, d, J = 7.6 Hz), 6.68-6.74 (2H, m), 6.76-6.82 (1H, m), 6.92-7.06 (3H, m ), 7.12-7.20 (1H, m), 7.22-7.29 (1H, m), 7.39-7.44 (1H, m), 7.95 (1H, d, J = 8.3Hz), 9.49 (1H, s), 9.58 ( 1H, s), 9.62 (1H, s), 13.08 (1H, s).

Examples 279, 280
In the same manner as in Example 278, the compounds shown in Table 36 were obtained.

2-anilino-4- (3-hydroxyphenyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.75-6.81 (1H, m), 6.91-6.96 (1H, m), 6.97-7.04 (2H, m), 7.11 (1H, t, J = 7.3Hz ), 7.24 (1H, t, J = 7.9Hz), 7.29-7.43 (5H, m), 7.97 (1H, d, J = 8.3Hz), 9.57 (1H, s), 9.68 (1H, s), 13.09 (1H, s).

4- (3-hydroxyphenyl) -2- (2-methylanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.24 (3H, s), 6.74-6.79 (1H, m), 6.86-6.90 (1H, m), 6.91-7.03 (3H, m), 7.07-7.14 (1H, m), 7.18-7.29 (2H, m), 7.34 (1H, d, J = 7.6Hz), 7.37-7.42 (1H, m), 7.96 (1H, d, J = 8.3Hz), 9.56 ( 2H, s), 13.05 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（３−（ｔｅｒｔ−ブトキシカルボニルオキシ）フェニル）ベンゾアート0.12gおよび炭酸セシウム0.25gのトルエン3.0mL懸濁液に、室温で１−ヨード−３，４−メチレンジオキシベンゼン0.15g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）2.9mgおよび酢酸パラジウム1.4mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）2.9mgおよび酢酸パラジウム1.4mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（３−（ｔｅｒｔ−ブトキシカルボニルオキシ）フェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（３−（ｔｅｒｔ−ブトキシカルボニルオキシ）フェニル）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-90％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、黄色固体の２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（３−ヒドロキシフェニル）安息香酸17mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.04(2H,s),6.75-6.80(2H,m),6.88-6.98(5H,m),7.11(1H,d,J=1.7Hz),7.23(1H,t,J=7.9Hz),7.92(1H,d,J=8.3Hz),9.47(1H,s),9.56(1H,s),12.99(1H,s).Example 281

tert-Butyl-2-amino-4- (3- (tert-butoxycarbonyloxy) phenyl) benzoate 0.12 g and cesium carbonate 0.25 g in toluene 3.0 mL suspension at room temperature with 1-iodo-3,4- Add 0.15 g of methylenedioxybenzene, 7.4 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 2.9 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.4 mg of palladium acetate. Stir at 24 ° C. for 24 hours. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.4 mg), tris (dibenzylideneacetone) dipalladium (0) (2.9 mg) and palladium acetate (1.4 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((benzo-1,3-dioxole). -5-yl) amino) -4- (3- (tert-butoxycarbonyloxy) phenyl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzo-1,3-dioxol-5-yl) amino) -4- (3- (tert-butoxycarbonyloxy) phenyl) benzoate, 5.0 mL of trifluoroacetic acid was added. The mixture was further stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 50-90% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((benzo 17 mg of -1,3-dioxol-5-yl) amino) -4- (3-hydroxyphenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.04 (2H, s), 6.75-6.80 (2H, m), 6.88-6.98 (5H, m), 7.11 (1H, d, J = 1.7 Hz), 7.23 (1H, t, J = 7.9Hz), 7.92 (1H, d, J = 8.3Hz), 9.47 (1H, s), 9.56 (1H, s), 12.99 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（３−（ｔｅｒｔ−ブトキシカルボニルオキシ）フェニル）ベンゾアート0.12gおよび炭酸セシウム0.25gのトルエン3.0mL懸濁液に、室温で５−ブロモベンゾチオフェン0.13g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）2.9mgおよび酢酸パラジウム1.4mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）2.9mgおよび酢酸パラジウム1.4mgを加え、110℃で21時間攪拌した。炭酸セシウム51mg、５−ブロモベンゾチオフェン33mg、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル7.4mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）2.9mgおよび酢酸パラジウム1.4mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（３−（ｔｅｒｔ−ブトキシカルボニルオキシ）フェニル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（３−（ｔｅｒｔ−ブトキシカルボニルオキシ）フェニル）ベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（（ベンゾチオフェン−５−イル）アミノ）−４−（３−ヒドロキシフェニル）安息香酸30mgを得た。
¹H-NMR(DMSO-d₆)δ値：6.76(1H,dd,J=8.1,1.9Hz),6.91(1H,s),6.95-7.03(2H,m),7.22(1H,t,J=7.8Hz),7.32-7.38(2H,m),7.44(1H,d,J=5.4Hz),7.79(1H,d,J=5.4Hz),7.83(1H,d,J=2.0Hz),7.98(1H,d,J=8.3Hz),8.01(1H,d,J=8.8Hz),9.54(1H,s),9.75(1H,s),13.00-13.15(1H,broad).Example 282

To a suspension of 0.12 g of tert-butyl = 2-amino-4- (3- (tert-butoxycarbonyloxy) phenyl) benzoate and 0.25 g of cesium carbonate in 3.0 mL of toluene was added 0.13 g of 5-bromobenzothiophene at room temperature, 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.4 mg), tris (dibenzylideneacetone) dipalladium (0) (2.9 mg) and palladium acetate (1.4 mg) were added, and the mixture was stirred at 110 ° C. for 24 hours. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (7.4 mg), tris (dibenzylideneacetone) dipalladium (0) (2.9 mg) and palladium acetate (1.4 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. Cesium carbonate 51 mg, 5-bromobenzothiophene 33 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 7.4 mg, tris (dibenzylideneacetone) dipalladium (0) 2.9 mg and palladium acetate 1.4 mg And stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((benzothiophen-5-yl). Amino) -4- (3- (tert-butoxycarbonyloxy) phenyl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzothiophen-5-yl) amino) -4- (3- (tert-butoxycarbonyloxy) phenyl) benzoate, 5.0 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature. Stir for hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 2-((benzothiophen-5-yl) amino) -4- (3-hydroxy as a yellow solid. 30 mg of phenyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 6.76 (1H, dd, J = 8.1, 1.9 Hz), 6.91 (1H, s), 6.95-7.03 (2H, m), 7.22 (1H, t, J = 7.8Hz), 7.32-7.38 (2H, m), 7.44 (1H, d, J = 5.4Hz), 7.79 (1H, d, J = 5.4Hz), 7.83 (1H, d, J = 2.0Hz), 7.98 (1H, d, J = 8.3Hz), 8.01 (1H, d, J = 8.8Hz), 9.54 (1H, s), 9.75 (1H, s), 13.00-13.15 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−（インドリン−１−イル）ベンゾアート0.12gのトルエン3.0mL溶液に、室温で１−ブロモ−３，４−メチレンジオキシベンゼン0.12mL、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で6時間攪拌した。室温でトリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で18時間30分間攪拌した。１−ブロモ−３，４−メチレンジオキシベンゼン0.12mL、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で22時間攪拌した。反応混合物を室温まで冷却した後、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で20時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（インドリン−１−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（インドリン−１−イル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、白色固体の２−（（ベンゾ−１，３−ジオキソール−５−イル）アミノ）−４−（インドリン−１−イル）安息香酸31mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.06(2H,t,J=8.5Hz),3.90(2H,t,J=8.5Hz),6.04(2H,s),6.55-6.60(1H,m),6.67-6.71(1H,m),6.75-6.81(2H,m),6.92-6.97(2H,m),7.02-7.12(2H,m),7.19(1H,d,J=7.3Hz),7.82(1H,d,J=8.8Hz),9.51(1H,s),12.45-12.55(1H,broad).Example 283

To a 3.0 mL toluene solution of 0.12 g of tert-butyl = 2-amino-4- (indoline-1-yl) benzoate at room temperature, 0.12 mL of 1-bromo-3,4-methylenedioxybenzene, 0.26 g of cesium carbonate, Tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 110 ° C. for 6 hours. At room temperature, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added, and the reaction was carried out at 110 ° C. for 18 hours 30 Stir for minutes. 1-bromo-3,4-methylenedioxybenzene 0.12 mL, cesium carbonate 0.26 g, tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′ , 6'-triisopropylbiphenyl 9.5 mg was added, and the mixture was stirred at 110 ° C for 22 hours. After cooling the reaction mixture to room temperature, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added. And stirred at 110 ° C. for 20 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((benzo-1,3-dioxole). -5-yl) amino) -4- (indoline-1-yl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzo-1,3-dioxol-5-yl) amino) -4- (indoline-1-yl) benzoate, 10 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. Stir. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue, the solid was collected by filtration, and white solid 2-((benzo-1,3-dioxol-5-yl) amino) -4- 31 mg of (indoline-1-yl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.06 (2H, t, J = 8.5 Hz), 3.90 (2H, t, J = 8.5 Hz), 6.04 (2H, s), 6.55-6.60 (1H, m), 6.67-6.71 (1H, m), 6.75-6.81 (2H, m), 6.92-6.97 (2H, m), 7.02-7.12 (2H, m), 7.19 (1H, d, J = 7.3Hz) , 7.82 (1H, d, J = 8.8Hz), 9.51 (1H, s), 12.45-12.55 (1H, broad).

Examples 284, 285
In the same manner as in Example 283, the compounds shown in Table 37 were obtained.

2-anilino-4- (indoline-1-yl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.07 (2H, t, J = 8.4 Hz), 3.93 (2H, t, J = 8.4 Hz), 6.65 (1H, dd, J = 8.9, 2.3 Hz) , 6.79 (1H, t, J = 7.3Hz), 6.90 (1H, d, J = 2.2Hz), 7.04-7.17 (3H, m), 7.19 (1H, d, J = 7.0Hz), 7.30-7.36 ( 2H, m), 7.36-7.44 (2H, m), 7.86 (1H, d, J = 9.0Hz), 9.76 (1H, s), 12.40-12.70 (1H, broad).

4- (Indoline-1-yl) -2- (2-methylanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.23 (3H, s), 3.05 (2H, t, J = 8.4 Hz), 3.88 (2H, t, J = 8.4 Hz), 6.56-6.63 (2H, m), 6.77 (1H, t, J = 7.1Hz), 6.99-7.12 (3H, m), 7.18 (1H, d, J = 7.3Hz), 7.27 (1H, t, J = 7.4Hz), 7.32 ( 1H, d, J = 7.6Hz), 7.43 (1H, d, J = 7.8Hz), 7.85 (1H, d, J = 9.5Hz), 9.61 (1H, s), 12.52 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（インドリン−１−イル）ベンゾアート0.12gの２−メチル−２−プロパノール3.0mL溶液に、室温で３−ヨードフェノール0.22g、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、70℃で12時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、70℃で7時間攪拌した。炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、70℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（（３−ヒドロキシフェニル）アミノ）−４−（インドリン−１−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（３−ヒドロキシフェニル）アミノ）−４−（インドリン−１−イル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-90％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（（３−ヒドロキシフェニル）アミノ）−４−（インドリン−１−イル）安息香酸13mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.08(2H,t,J=8.4Hz),3.94(2H,t,J=8.4Hz),6.46-6.52(1H,m),6.64(1H,dd,J=8.9,2.1Hz),6.69-6.74(2H,m),6.79(1H,t,J=7.3Hz),6.93-6.97(1H,m),7.07(1H,t,J=7.7Hz),7.13-7.23(3H,m),7.85(1H,d,J=9.0Hz),9.47(1H,s),9.68(1H,s),12.55(1H,s).Example 286

tert-Butyl-2-amino-4- (indoline-1-yl) benzoate 0.12 g in 2-methyl-2-propanol 3.0 mL solution at room temperature 0.23-g 3-iodophenol, cesium carbonate 0.26 g, tris ( Dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 70 ° C. for 12 hours. Tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 70 ° C. for 7 hours. Add 0.26 g of cesium carbonate, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl at 70 ° C. Stir for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2 ((3-hydroxyphenyl) amino). -4- (Indolin-1-yl) benzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2-((3-hydroxyphenyl) amino) -4- (indoline-1-yl) benzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 50-90% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((3 -Hydroxyphenyl) amino) -4- (indoline-1-yl) benzoic acid 13 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.08 (2H, t, J = 8.4 Hz), 3.94 (2H, t, J = 8.4 Hz), 6.46-6.52 (1H, m), 6.64 (1H, dd, J = 8.9,2.1Hz), 6.69-6.74 (2H, m), 6.79 (1H, t, J = 7.3Hz), 6.93-6.97 (1H, m), 7.07 (1H, t, J = 7.7Hz ), 7.13-7.23 (3H, m), 7.85 (1H, d, J = 9.0Hz), 9.47 (1H, s), 9.68 (1H, s), 12.55 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（インドリン−１−イル）ベンゾアート0.12gのトルエン3.0mL溶液に、室温で５−ブロモベンゾチオフェン0.21g、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で12時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で6時間攪拌した。室温で５−ブロモベンゾチオフェン0.21g、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（インドリン−１−イル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（インドリン−１−イル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、褐色固体の２−（（ベンゾチオフェン−５−イル）アミノ）−４−（インドリン−１−イル）安息香酸67mgを得た。
¹H-NMR(DMSO-d₆)δ値：3.05(2H,t,J=8.4Hz),3.91(2H,t,J=8.4Hz),6.62(1H,dd,J=9.0,2.2Hz),6.76(1H,t,J=7.4Hz),6.91(1H,d,J=2.2Hz),7.02(1H,t,J=7.8Hz),7.13-7.20(2H,m),7.34(1H,dd,J=8.5,1.9Hz),7.45(1H,d,J=5.4Hz),7.79(1H,d,J=5.4Hz),7.84-7.91(2H,m),8.00(1H,d,J=8.5Hz),9.83(1H,s),12.56(1H,s).Example 287

tert-Butyl-2-amino-4- (indoline-1-yl) benzoate 0.12 g in a toluene 3.0 mL solution at room temperature, 0.21 g of 5-bromobenzothiophene, 0.26 g of cesium carbonate, tris (dibenzylideneacetone) di 3.7 mg of palladium (0), 1.8 mg of palladium acetate, and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added, and the mixture was stirred at 110 ° C. for 12 hours. Tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 110 ° C. for 6 hours. At room temperature, 0.21 g of 5-bromobenzothiophene, 0.26 g of cesium carbonate, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-tri 9.5 mg of isopropyl biphenyl was added, and the mixture was stirred at 110 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((benzothiophen-5-yl). Amino) -4- (indoline-1-yl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzothiophen-5-yl) amino) -4- (indoline-1-yl) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, methanol was added to the resulting residue, the solid was collected by filtration, and 2-((benzothiophen-5-yl) amino) -4- (indoline-1-) as a brown solid. I) 67 mg of benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 3.05 (2H, t, J = 8.4 Hz), 3.91 (2H, t, J = 8.4 Hz), 6.62 (1H, dd, J = 9.0, 2.2 Hz) , 6.76 (1H, t, J = 7.4Hz), 6.91 (1H, d, J = 2.2Hz), 7.02 (1H, t, J = 7.8Hz), 7.13-7.20 (2H, m), 7.34 (1H, dd, J = 8.5,1.9Hz), 7.45 (1H, d, J = 5.4Hz), 7.79 (1H, d, J = 5.4Hz), 7.84-7.91 (2H, m), 8.00 (1H, d, J = 8.5Hz), 9.83 (1H, s), 12.56 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（２−（３−メトキシフェニル）エチル）ベンゾアート0.13gのトルエン3.0mL溶液に、ヨードベンゼン0.11mL、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で6時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で18時間30分間攪拌した。ヨードベンゼン0.11mL、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で22時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で20時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−アニリノ−４−（２−（３−メトキシフェニル）エチル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−アニリノ−４−（２−（３−メトキシフェニル）エチル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；65-100％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−アニリノ−４−（２−（３−メトキシフェニル）エチル）安息香酸4.2mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.82(4H,s),3.70(3H,s),6.66-6.80(4H,m),6.97(1H,s),7.00-7.10(3H,m),7.17(1H,t,J=7.9Hz),7.31(2H,t,J=7.7Hz),7.81(1H,d,J=8.0Hz),9.61(1H,s),12.85-13.05(1H,broad).Example 288

tert-Butyl-2-amino-4- (2- (3-methoxyphenyl) ethyl) benzoate 0.13 g in toluene 3.0 mL solution, iodobenzene 0.11 mL, cesium carbonate 0.26 g, tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg, and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 110 ° C. for 6 hours. Add 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, and stir at 110 ° C. for 18 hours and 30 minutes. did. 0.11 mL of iodobenzene, 0.26 g of cesium carbonate, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl The mixture was further stirred at 110 ° C. for 22 hours. Tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 110 ° C. for 20 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-anilino-4- (2- (3 -Methoxyphenyl) ethyl) benzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2-anilino-4- (2- (3-methoxyphenyl) ethyl) benzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 65-100% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-anilino-4 as a white solid. 4.2 mg of-(2- (3-methoxyphenyl) ethyl) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.82 (4H, s), 3.70 (3H, s), 6.66-6.80 (4H, m), 6.97 (1H, s), 7.00-7.10 (3H, m ), 7.17 (1H, t, J = 7.9Hz), 7.31 (2H, t, J = 7.7Hz), 7.81 (1H, d, J = 8.0Hz), 9.61 (1H, s), 12.85-13.05 (1H , broad).

Examples 289, 290
In the same manner as in Example 288, the compounds shown in Table 38 were obtained.

2-((Benzo-1,3-dioxol-5-yl) amino) -4- (2- (3-methoxyphenyl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78 (4H, s), 3.70 (3H, s), 6.03 (2H, s), 6.56 (1H, dd, J = 8.3, 2.2 Hz), 6.62 ( 1H, d, J = 8.0Hz), 6.71-6.78 (5H, m), 6.86 (1H, d, J = 8.3Hz), 7.16 (1H, t, J = 7.7Hz), 7.77 (1H, d, J = 8.0Hz), 9.40 (1H, s), 12.82 (1H, s).

4- (2- (3-methoxyphenyl) ethyl) -2- (2-methylanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.16 (3H, s), 2.78 (4H, s), 3.69 (3H, s), 6.63-6.77 (5H, m), 7.00-7.07 (1H, m ), 7.07-7.20 (3H, m), 7.27 (1H, d, J = 7.3Hz), 7.81 (1H, d, J = 8.1Hz), 9.49 (1H, s), 12.88 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（２−（３−メトキシフェニル）エチル）ベンゾアート0.13gの２−メチル−２−プロパノール3.0mL溶液に、室温で３−ヨードフェノール0.22g、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、70℃で12時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、70℃で7時間攪拌した。炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、70℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝２−（（３−ヒドロキシフェニル）アミノ）−４−（２−（３−メトキシフェニル）エチル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（３−ヒドロキシフェニル）アミノ）−４−（２−（３−メトキシフェニル）エチル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-90％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の２−（（３−ヒドロキシフェニル）アミノ）−４−（２−（３−メトキシフェニル）エチル）安息香酸17mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.82(4H,s),3.70(3H,s),6.45(1H,dd,J=7.9,1.8Hz),6.49-6.54(1H,m),6.57-6.61(1H,m),6.65-6.70(1H,m),6.72-6.79(3H,m),7.05-7.12(2H,m),7.17(1H,t,J=8.0Hz),7.80(1H,d,J=8.3Hz),9.42(1H,s),9.55(1H,s),12.90(1H,s).Example 291

tert-Butyl-2-amino-4- (2- (3-methoxyphenyl) ethyl) benzoate 0.13 g in 2-methyl-2-propanol 3.0 mL solution at room temperature 0.22 g 3-iodophenol, cesium carbonate 0.26 g, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl were added, and the mixture was stirred at 70 ° C. for 12 hours. did. Tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 70 ° C. for 7 hours. Add 0.26 g of cesium carbonate, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl at 70 ° C. Stir for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 4: 1], and tert-butyl = 2 ((3-hydroxyphenyl) amino). -4- (2- (3-methoxyphenyl) ethyl) benzoate was obtained.
10 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2-((3-hydroxyphenyl) amino) -4- (2- (3-methoxyphenyl) ethyl) benzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase silica gel column chromatography [eluent: 50-90% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 2-((3 -Hydroxyphenyl) amino) -4- (2- (3-methoxyphenyl) ethyl) benzoic acid 17 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.82 (4H, s), 3.70 (3H, s), 6.45 (1H, dd, J = 7.9, 1.8 Hz), 6.49-6.54 (1H, m), 6.57-6.61 (1H, m), 6.65-6.70 (1H, m), 6.72-6.79 (3H, m), 7.05-7.12 (2H, m), 7.17 (1H, t, J = 8.0Hz), 7.80 ( 1H, d, J = 8.3Hz), 9.42 (1H, s), 9.55 (1H, s), 12.90 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−（２−（３−メトキシフェニル）エチル）ベンゾアート0.13gのトルエン3.0mL溶液に、室温で５−ブロモベンゾチオフェン0.21g、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で12時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で6時間攪拌した。５−ブロモベンゾチオフェン0.21g、炭酸セシウム0.26g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で12時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（２−（３−メトキシフェニル）エチル）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（ベンゾチオフェン−５−イル）アミノ）−４−（２−（３−メトキシフェニル）エチル）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、褐色固体の２−（（ベンゾチオフェン−５−イル）アミノ）−４−（２−（３−メトキシフェニル）エチル）安息香酸61mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.80(4H,s),3.69(3H,s),6.66-6.82(4H,m),6.97(1H,s),7.10-7.20(2H,m),7.39(1H,d,J=5.5Hz),7.65(1H,d,J=1.9Hz),7.78(1H,d,J=5.5Hz),7.82(1H,d,J=8.3Hz),7.93(1H,d,J=8.8Hz),9.68(1H,s),12.80-13.00(1H,broad).Example 292

tert-Butyl-2-amino-4- (2- (3-methoxyphenyl) ethyl) benzoate 0.13 g in toluene (3.0 mL) was stirred at room temperature with 0.21 g of 5-bromobenzothiophene, 0.26 g of cesium carbonate, Benzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 110 ° C. for 12 hours. Tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 110 ° C. for 6 hours. 5-bromobenzothiophene 0.21 g, cesium carbonate 0.26 g, tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg was added and stirred at 110 ° C. for 12 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((benzothiophen-5-yl). Amino) -4- (2- (3-methoxyphenyl) ethyl) benzoate was obtained.
To the obtained tert-butyl = 2-((benzothiophen-5-yl) amino) -4- (2- (3-methoxyphenyl) ethyl) benzoate, 10 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. did. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 2-((benzothiophen-5-yl) amino) -4- (2- ( 61 mg of 3-methoxyphenyl) ethyl) benzoic acid were obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80 (4H, s), 3.69 (3H, s), 6.66-6.82 (4H, m), 6.97 (1H, s), 7.10-7.20 (2H, m ), 7.39 (1H, d, J = 5.5Hz), 7.65 (1H, d, J = 1.9Hz), 7.78 (1H, d, J = 5.5Hz), 7.82 (1H, d, J = 8.3Hz), 7.93 (1H, d, J = 8.8Hz), 9.68 (1H, s), 12.80-13.00 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−（２−（２，３−ジヒドロ［１，４］ベンゾジオキシン−６−イル）エチル）ベンゾアート0.14gのトルエン3.0mL溶液に、室温で３−ヨードフェノール0.22g、炭酸セシウム0.52g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で6時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で18時間30分間攪拌した。３−ヨードフェノール0.22g、炭酸セシウム0.52g、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で22時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム1.8mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mgを加え、110℃で20時間攪拌した。反応混合物を室温まで冷却した後、不溶物をろ去し、酢酸エチルおよび10％クエン酸水溶液を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝４：１］で精製し、ｔｅｒｔ−ブチル＝４−（２−（２，３−ジヒドロ［１，４］ベンゾジオキシン−６−イル）エチル）−２−（（３−ヒドロキシフェニル）アミノ）ベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝４−（２−（２，３−ジヒドロ［１，４］ベンゾジオキシン−６−イル）エチル）−２−（（３−ヒドロキシフェニル）アミノ）ベンゾアートに、トリフルオロ酢酸10mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；55-75％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製し、白色固体の４−（２−（２，３−ジヒドロ［１，４］ベンゾジオキシン−６−イル）エチル）−２−（（３−ヒドロキシフェニル）アミノ）安息香酸8.1mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.69-2.81(4H,m),4.18(4H,s),6.43-6.69(6H,m),6.73(1H,d,J=8.1Hz),7.05(1H,s),7.10(1H,t,J=7.9Hz),7.79(1H,d,J=8.1Hz),9.43(1H,s),9.55(1H,s),12.91(1H,s).Example 293

tert-Butyl-2-amino-4- (2- (2,3-dihydro [1,4] benzodioxin-6-yl) ethyl) benzoate 0.14 g in toluene 3.0 mL solution at room temperature with 3-iodophenol 0.22 g, cesium carbonate 0.52 g, tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, The mixture was stirred at 110 ° C. for 6 hours. Add 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, and stir at 110 ° C. for 18 hours and 30 minutes. did. 0.22 g of 3-iodophenol, 0.52 g of cesium carbonate, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), 1.8 mg of palladium acetate and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg was added and it stirred at 110 degreeC for 22 hours. Tris (dibenzylideneacetone) dipalladium (0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg were added, and the mixture was stirred at 110 ° C. for 20 hours. The reaction mixture was cooled to room temperature, insoluble material was removed by filtration, and ethyl acetate and 10% aqueous citric acid solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 4: 1], and tert-butyl = 4- (2- (2,3-dihydro [1,4] Benzodioxin-6-yl) ethyl) -2-((3-hydroxyphenyl) amino) benzoate was obtained.
To the obtained tert-butyl = 4- (2- (2,3-dihydro [1,4] benzodioxin-6-yl) ethyl) -2-((3-hydroxyphenyl) amino) benzoate, trifluoro 10 mL of acetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 55-75% acetonitrile / 0.1% aqueous trifluoroacetic acid solution] to give 4- (2- 8.1 mg of (2,3-dihydro [1,4] benzodioxin-6-yl) ethyl) -2-((3-hydroxyphenyl) amino) benzoic acid was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.69-2.81 (4H, m), 4.18 (4H, s), 6.43-6.69 (6H, m), 6.73 (1H, d, J = 8.1 Hz), 7.05 (1H, s), 7.10 (1H, t, J = 7.9Hz), 7.79 (1H, d, J = 8.1Hz), 9.43 (1H, s), 9.55 (1H, s), 12.91 (1H, s ).

Examples 294-296
In the same manner as in Example 293, the compounds shown in Table 39 were obtained.

4- (2- (2,3-dihydro [1,4] benzodioxin-6-yl) ethyl) -2- (2-methylanilino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.17 (3H, s), 2.66-2.76 (4H, m), 4.18 (4H, s), 6.57-6.69 (4H, m), 6.72 (1H, d , J = 8.0Hz), 7.00-7.07 (1H, m), 7.10-7.20 (2H, m), 7.27 (1H, d, J = 7.6Hz), 7.80 (1H, d, J = 8.1Hz), 9.49 (1H, s), 12.88 (1H, s).

2-((Benzo-1,3-dioxol-5-yl) amino) -4- (2- (2,3-dihydro [1,4] benzodioxin-6-yl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.66-2.77 (4H, m), 4.18 (4H, s), 6.03 (2H, s), 6.55-6.66 (4H, m), 6.72 (1H, d , J = 8.3Hz), 6.74-6.81 (2H, m), 6.87 (1H, d, J = 8.0Hz), 7.77 (1H, d, J = 8.3Hz), 9.40 (1H, s), 12.81 (1H , s).

2-anilino-4- (2- (2,3-dihydro [1,4] benzodioxin-6-yl) ethyl) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.69-2.80 (4H, m), 4.18 (4H, s), 6.60-6.71 (3H, m), 6.74 (1H, d, J = 7.8 Hz), 6.96 (1H, s), 7.02-7.12 (3H, m), 7.27-7.37 (2H, m), 7.81 (1H, d, J = 8.0Hz), 9.61 (1H, s), 12.91 (1H, s) .

４−ブロモビフェニル0.43gのトルエン3.0mL溶液に、室温で２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル17mg、ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.20g、炭酸セシウム0.48g、酢酸パラジウム1.7mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）6.8mgを加え、5時間40分間加熱還流した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル17mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）6.8mgおよび酢酸パラジウム1.7mgを加え、2時間20分間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝５０：１］で精製し、淡黄色固体のｔｅｒｔ−ブチル＝２−（（ビフェニル−４−イル）アミノ）−４−フェニルベンゾアート0.24gを得た。
¹H-NMR(CDCl₃)δ値：1.63(9H,s),6.98(1H,dd,J=8.4,1.8Hz),7.28-7.47(8H,m),7.53-7.64(7H,m),8.00(1H,d,J=8.3Hz),9.69(1H,s).Example 297

To a 3.0 mL toluene solution of 0.43 g of 4-bromobiphenyl, 17 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl at room temperature, 0.20 g of tert-butyl = 2-amino-4-phenylbenzoate Then, 0.48 g of cesium carbonate, 1.7 mg of palladium acetate and 6.8 mg of tris (dibenzylideneacetone) dipalladium (0) were added, and the mixture was heated to reflux for 5 hours and 40 minutes. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 17 mg, tris (dibenzylideneacetone) dipalladium (0) 6.8 mg and palladium acetate 1.7 mg were added, and the mixture was heated to reflux for 2 hours and 20 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 50: 1], and tert-butyl = 2-(( 0.24 g of biphenyl-4-yl) amino) -4-phenylbenzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 6.98 (1H, dd, J = 8.4, 1.8 Hz), 7.28-7.47 (8H, m), 7.53-7.64 (7H, m), 8.00 (1H, d, J = 8.3Hz), 9.69 (1H, s).

Examples 298-306
In the same manner as in Example 297, the compounds shown in Table 40 were obtained.

tert-butyl = 2-((biphenyl-3-yl) amino) -4-phenylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 6.97 (1H, dd, J = 8.3, 1.7 Hz), 7.26-7.64 (15H, m), 8.00 (1H, d, J = 8.3) Hz), 9.71 (1H, s).

tert-butyl = 2-((biphenyl-2-yl) amino) -4-phenylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.47 (9H, s), 6.90 (1H, dd, J = 8.3, 1.7 Hz), 7.19 (1H, td, J = 7.6, 1.2 Hz), 7.26-7.60 ( 14H, m), 7.92 (1H, d, J = 8.3Hz), 9.19 (1H, s).

tert-butyl = 2-((isoquinolin-4-yl) amino) -4-phenylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.66 (9H, s), 7.26-7.30 (1H, m), 7.37-7.50 (3H, m), 7.50-7.58 (2H, m), 7.62-7.66 (1H) , m), 7.97 (1H, t, J = 7.4Hz), 8.10-8.18 (2H, m), 8.25 (1H, d, J = 8.3Hz), 8.44 (1H, d, J = 8.6Hz), 8.63 (1H, s), 9.04 (1H, s), 10.82 (1H, s).

tert-Butyl = 4-Phenyl-2-((quinolin-8-yl) amino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.66 (9H, s), 7.10 (1H, dd, J = 8.3, 1.7 Hz), 7.33-7.40 (2H, m), 7.42-7.48 (4H, m), 7.58-7.62 (2H, m), 7.78-7.83 (1H, m), 8.01 (1H, d, J = 1.7Hz), 8.06 (1H, d, J = 8.3Hz), 8.14 (1H, dd, J = 8.3, 1.7 Hz), 8.93 (1 H, dd, J = 4.1, 1.7 Hz), 10.72 (1 H, s).

tert-butyl = 4-phenyl-2- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenylamino) benzoate
¹ H-NMR (DMSO-d ₆ ) δ value: 1.46-1.94 (6H, m), 1.59 (9H, s), 3.52-3.60 (1H, m), 3.76-3.84 (1H, m), 5.43 (1H , t, J = 3.3Hz), 7.00 (1H, dd, J = 8.3,1.7Hz), 7.02-7.08 (2H, m), 7.19 (1H, d, J = 1.7Hz), 7.22-7.28 (2H, m), 7.36-7.48 (3H, m), 7.50-7.56 (2H, m), 7.91 (1H, d, J = 8.3Hz), 9.33 (1H, s).

tert-butyl = 4-phenyl-2-((quinolin-3-yl) amino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.65 (9H, s), 7.06 (1H, dd, J = 8.3, 1.7 Hz), 7.32-7.44 (3H, m), 7.48-7.58 (4H, m), 7.58-7.64 (1H, m), 7.73 (1H, dd, J = 8.0,1.2Hz), 7.99 (1H, d, J = 2.4Hz), 8.02-8.08 (2H, m), 8.94 (1H, d, J = 2.4Hz), 9.91 (1H, s).

tert-butyl = 2-((isoquinolin-5-yl) amino) -4-phenylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.66 (9H, s), 7.00 (1H, dd, J = 8.4, 1.8 Hz), 7.24-7.27 (1H, m), 7.30-7.40 (3H, m), 7.40-7.46 (2H, m), 7.59 (1H, t, J = 7.8Hz), 7.78 (2H, t, J = 7.8Hz), 7.94 (1H, d, J = 6.1Hz), 8.05 (1H, d , J = 8.3Hz), 8.56 (1H, d, J = 5.8Hz), 9.28 (1H, s), 10.07 (1H, s).

tert-butyl = 4-phenyl-2- (2-((tetrahydro-2H-pyran-2-yl) oxy) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.51-2.17 (6H, m), 1.60 (9H, s), 3.55-3.62 (1H, m), 3.93 (1H, td, J = 11.1,2.8 Hz), 5.51 (1H, t, J = 2.8Hz), 6.93-7.01 (3H, m), 7.17-7.24 (1H, m), 7.32-7.45 (3H, m), 7.50-7.60 (4H, m), 7.99 ( 1H, d, J = 8.3Hz), 9.89 (1H, s).

tert-butyl = 4-phenyl-2- (3- (1H-pyrazol-1-yl) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 6.46 (1H, dd, J = 2.4, 2.0 Hz), 7.00 (1H, dd, J = 8.3, 1.7 Hz), 7.22-7.28 ( 1H, m), 7.32-7.45 (5H, m), 7.52-7.60 (3H, m), 7.65-7.69 (1H, m), 7.70-7.73 (1H, m), 7.91 (1H, d, J = 2.4 Hz), 8.00 (1H, d, J = 8.3Hz), 9.75 (1H, s).

４−ブロモビフェニル0.12gのトルエン1.0mL溶液に、室温で２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル4.8mg、ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート60mg、炭酸セシウム0.13g、酢酸パラジウム0.50mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）1.8mgを加え、5時間30分間加熱還流した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル4.8mg、酢酸パラジウム0.50mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）1.8mgを加え、7時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２００：１］で精製し、黄色油状物のｔｅｒｔ−ブチル＝２−（（ビフェニル−４−イル）アミノ）−４−フェネチルベンゾアート50mgを得た。
¹H-NMR(CDCl₃)δ値：1.60(9H,s),2.80-2.94(4H,m),6.58(1H,dd,J=8.2,1.6Hz),7.06(1H,d,J=1.2Hz),7.11-7.36(8H,m),7.40-7.47(2H,m),7.49-7.55(2H,m),7.56-7.63(2H,m),7.85(1H,d,J=8.3Hz),9.58(1H,s).Example 307

To a 1.0 mL toluene solution of 0.12 g of 4-bromobiphenyl, 4.8 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and 60 mg of tert-butyl = 2-amino-4-phenethylbenzoate at room temperature Then, 0.13 g of cesium carbonate, 0.50 mg of palladium acetate and 1.8 mg of tris (dibenzylideneacetone) dipalladium (0) were added, and the mixture was heated to reflux for 5 hours and 30 minutes. 2-Dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (4.8 mg), palladium acetate (0.50 mg) and tris (dibenzylideneacetone) dipalladium (0) (1.8 mg) were added, and the mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 200: 1], and tert-butyl = 2-(( 50 mg of biphenyl-4-yl) amino) -4-phenethylbenzoate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.80-2.94 (4H, m), 6.58 (1H, dd, J = 8.2, 1.6 Hz), 7.06 (1H, d, J = 1.2 Hz), 7.11-7.36 (8H, m), 7.40-7.47 (2H, m), 7.49-7.55 (2H, m), 7.56-7.63 (2H, m), 7.85 (1H, d, J = 8.3Hz) , 9.58 (1H, s).

Examples 308-318
In the same manner as in Example 307, the compounds shown in Table 41 were obtained.

tert-butyl = 2-((biphenyl-3-yl) amino) -4-phenethylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.78-2.92 (4H, m), 6.58 (1H, dd, J = 8.3, 1.6 Hz), 7.08-7.21 (5H, m), 7.23-7.62 (10H, m), 7.84 (1H, d, J = 8.3Hz), 9.61 (1H, s).

tert-butyl = 2-((biphenyl-2-yl) amino) -4-phenethylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.44 (9H, s), 2.74-2.88 (4H, m), 6.52 (1H, dd, J = 8.3, 1.5 Hz), 6.89 (1H, d, J = 1.5 Hz), 7.10-7.23 (4H, m), 7.24-7.43 (10H, m), 7.77 (1H, d, J = 8.3Hz), 9.08 (1H, s).

tert-butyl = 2-((quinolin-8-yl) amino) -4-phenethylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 2.86-3.00 (4H, m), 6.71 (1H, dd, J = 8.2, 1.6 Hz), 7.14-7.46 (10H, m), 7.90 (1H, d, J = 8.3Hz), 8.10 (1H, dd, J = 8.3, 1.7Hz), 8.89 (1H, dd, J = 4.3, 1.8Hz), 10.61 (1H, s).

tert-butyl 4-phenethyl-2- (4-((tetrahydro-2H-pyran-2-yl) oxy) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.54-1.76 (3H, m), 1.59 (9H, s), 1.82-1.94 (2H, m), 1.94-2.08 (1H, m), 2.74-2.88 (4H , m), 3.60-3.65 (1H, m), 3.93-4.01 (1H, m), 5.38 (1H, t, J = 3.3Hz), 6.50 (1H, dd, J = 8.2, 1.5Hz), 6.79 ( 1H, d, J = 1.5Hz), 6.96-7.06 (4H, m), 7.10-7.30 (5H, m), 7.81 (1H, d, J = 8.0Hz), 9.34 (1H, s).

tert-Butyl = 4-phenethyl-2-((quinolin-3-yl) amino) benzoate
¹ H-NMR (DMSO-d ₆ ) δ value: 1.56 (9H, s), 2.87 (4H, s), 6.80 (1H, d, J = 8.3 Hz), 7.12-7.28 (6H, m), 7.54- 7.64 (2H, m), 7.82 (1H, d, J = 8.0Hz), 7.85 (1H, d, J = 8.3Hz), 7.93-8.00 (2H, m), 8.79 (1H, d, J = 2.4Hz ), 9.58 (1H, s).

tert-butyl = 2-((isoquinolin-5-yl) amino) -4-phenethylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 2.74-2.88 (4H, m), 6.63 (1H, dd, J = 8.2, 1.5 Hz), 6.80 (1H, d, J = 1.5 Hz), 7.06-7.12 (2H, m), 7.15-7.29 (3H, m), 7.45-7.55 (2H, m), 7.72 (1H, d, J = 7.6Hz), 7.86-7.92 (2H, m) , 8.53 (1H, d, J = 5.9Hz), 9.26 (1H, d, J = 0.8Hz), 9.99 (1H, s).

tert-butyl 4-phenethyl-2- (2-((tetrahydro-2H-pyran-2-yl) oxy) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.52-2.22 (6H, m), 1.58 (9H, s), 2.80-2.92 (4H, m), 3.55-3.63 (1H, m), 3.94 (1H, td , J = 11.2, 2.6Hz), 5.49 (1H, t, J = 2.8Hz), 6.57 (1H, dd, J = 8.3, 1.5Hz), 6.86-6.98 (2H, m), 7.10-7.32 (8H, m), 7.84 (1H, d, J = 8.3Hz), 9.81 (1H, s).

tert-Butyl = 4-phenethyl-2- (3- (1H-pyrazol-1-yl) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.80-2.94 (4H, m), 6.45 (1H, dd, J = 2.3, 1.8 Hz), 6.61 (1H, dd, J = 8.2 , 1.6Hz), 6.98-7.04 (1H, m), 7.08-7.38 (8H, m), 7.52-7.56 (1H, m), 7.71 (1H, d, J = 1.7Hz), 7.84 (1H, d, J = 8.2Hz), 7.88 (1H, d, J = 2.4Hz), 9.66 (1H, s).

tert-butyl = 4-phenethyl-2- (4- (1H-pyrazol-1-yl) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.79-2.92 (4H, m), 6.45-6.48 (1H, m), 6.59 (1H, dd, J = 8.3, 1.4 Hz), 6.95 (1H, d, J = 1.4Hz), 7.10-7.32 (7H, m), 7.56-7.62 (2H, m), 7.72 (1H, d, J = 1.5Hz), 7.84 (1H, d, J = 8.3Hz), 7.88 (1H, d, J = 2.4Hz), 9.57 (1H, s).

tert-Butyl = 4-phenethyl-2- (3- (1H-pyrrol-1-yl) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.80-2.94 (4H, m), 6.33 (2H, t, J = 2.2 Hz), 6.61 (1H, dd, J = 8.3, 1.6 Hz), 6.96 (1H, dd, J = 7.8,1.7Hz), 7.02-7.10 (4H, m), 7.12-7.34 (7H, m), 7.85 (1H, d, J = 8.3Hz), 9.62 (1H , s).

tert-Butyl = 4-phenethyl-2- (4- (1H-pyrrol-1-yl) phenylamino) benzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.80-2.92 (4H, m), 6.35 (2H, t, J = 2.1 Hz), 6.59 (1H, dd, J = 8.2, 1.6 Hz), 6.93 (1H, d, J = 1.6Hz), 7.04-7.34 (11H, m), 7.84 (1H, d, J = 8.2Hz), 9.53 (1H, s).

４−ブロモイソキノリン0.12gのトルエン1.0mL溶液に、室温で２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mg、ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート59mg、炭酸セシウム0.13g、酢酸パラジウム0.90mgおよびトリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mgを加え、7時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、1.0mol/L塩酸および飽和塩化ナトリウム水溶液で順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に、酢酸エチルおよびヘキサンを加え、固形物をろ取し、黄色固体のｔｅｒｔ−ブチル＝２−（（イソキノリン−４−イル）アミノ）−４−フェネチルベンゾアート34mgを得た。
¹H-NMR(CDCl₃)δ値：1.63(9H,s),2.88-3.02(4H,m),6.88(1H,d,J=8.0Hz),7.12-7.36(6H,m),7.94-8.00(2H,m),8.11-8.17(1H,m),8.25(1H,d,J=8.5Hz),8.33(1H,s),8.39(1H,d,J=8.6Hz),9.04(1H,s),10.82(1H,s).Example 319

To a solution of 0.12 g of 4-bromoisoquinoline in 1.0 mL of toluene at room temperature is 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 59 mg of tert-butyl = 2-amino-4-phenethylbenzoate. Then, 0.13 g of cesium carbonate, 0.90 mg of palladium acetate and 3.7 mg of tris (dibenzylideneacetone) dipalladium (0) were added, and the mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with 1.0 mol / L hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate and hexane were added to the obtained residue, and the solid substance was collected by filtration to obtain 34 mg of tert-butyl = 2-((isoquinolin-4-yl) amino) -4-phenethylbenzoate as a yellow solid. .
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 2.88-3.02 (4H, m), 6.88 (1H, d, J = 8.0 Hz), 7.12-7.36 (6H, m), 7.94 8.00 (2H, m), 8.11-8.17 (1H, m), 8.25 (1H, d, J = 8.5Hz), 8.33 (1H, s), 8.39 (1H, d, J = 8.6Hz), 9.04 (1H , s), 10.82 (1H, s).

１−フルオロ−２−ヨードベンゼン0.11gに、室温で２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム0.90mg、ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート54mg、炭酸セシウム0.13gおよびトルエン1.0mLを加え、9時間30分間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２００：１］で精製し、白色固体のｔｅｒｔ−ブチル＝２−（２−フルオロアニリノ）−４−フェニルベンゾアート42mgを得た。
¹H-NMR(CDCl₃)δ値：1.63(9H,s),6.99(1H,dd,J=8.3,1.7Hz),7.00-7.20(3H,m),7.32-7.56(7H,m),8.00(1H,d,J=8.3Hz),9.51(1H,s).Example 320

0.11 g of 1-fluoro-2-iodobenzene, 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), acetic acid at room temperature 0.90 mg of palladium, 54 mg of tert-butyl = 2-amino-4-phenylbenzoate, 0.13 g of cesium carbonate and 1.0 mL of toluene were added, and the mixture was heated to reflux for 9 hours 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 200: 1], and white solid tert-butyl = 2- (2- 42 mg of fluoroanilino) -4-phenylbenzoate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 6.99 (1H, dd, J = 8.3, 1.7 Hz), 7.00-7.20 (3H, m), 7.32-7.56 (7H, m), 8.00 (1H, d, J = 8.3Hz), 9.51 (1H, s).

実施例３２０と同様にして、以下の化合物を得た。
ｔｅｒｔ−ブチル＝２−（２−クロロアニリノ）−４−フェニルベンゾアート
¹H-NMR(CDCl₃)δ値：1.63(9H,s),6.98(1H,td,J=7.7,1.5Hz),7.02(1H,dd,J=8.3,1.7Hz),7.18-7.24(1H,m),7.32-7.48(5H,m),7.50-7.58(3H,m),8.00(1H,d,J=8.3Hz),9.63(1H,s).Example 321

In the same manner as in Example 320, the following compound was obtained.
tert-butyl = 2- (2-chloroanilino) -4-phenylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.63 (9H, s), 6.98 (1H, td, J = 7.7, 1.5 Hz), 7.02 (1H, dd, J = 8.3, 1.7 Hz), 7.18-7.24 ( 1H, m), 7.32-7.48 (5H, m), 7.50-7.58 (3H, m), 8.00 (1H, d, J = 8.3Hz), 9.63 (1H, s).

１−フルオロ−２−ヨードベンゼン0.11gに、室温で２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム0.90mg、ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート59mg、炭酸セシウム0.13gおよびおよびトルエン1.0mLを加え、9時間30分間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝２００：１］で精製し、無色油状物のｔｅｒｔ−ブチル＝２−（２−フルオロアニリノ）−４−フェネチルベンゾアート62mgを得た。
¹H-NMR(CDCl₃)δ値：1.60(9H,s),2.80-2.92(4H,m),6.61(1H,dd,J=8.1,1.7Hz),6.88(1H,s),6.95-7.06(2H,m),7.06-7.30(7H,m),7.84(1H,d,J=8.1Hz),9.40(1H,s).Example 322

0.11 g of 1-fluoro-2-iodobenzene, 9.5 mg of 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0), acetic acid at room temperature 0.90 mg of palladium, 59 mg of tert-butyl = 2-amino-4-phenethylbenzoate, 0.13 g of cesium carbonate, and 1.0 mL of toluene were added, and the mixture was heated to reflux for 9 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 200: 1], and tert-butyl = 2- (2 -Fluoroanilino) -4-phenethylbenzoate 62 mg was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.80-2.92 (4H, m), 6.61 (1H, dd, J = 8.1, 1.7 Hz), 6.88 (1H, s), 6.95 7.06 (2H, m), 7.06-7.30 (7H, m), 7.84 (1H, d, J = 8.1Hz), 9.40 (1H, s).

実施例３２２と同様にして、以下の化合物を得た。
ｔｅｒｔ−ブチル＝２−（２−クロロアニリノ）−４−フェネチルベンゾアート
¹H-NMR(CDCl₃)δ値：1.60(9H,s),2.80-2.92(4H,m),6.64(1H,dd,J=8.1,1.6Hz),6.90-6.96(2H,m),7.08-7.30(7H,m),7.40(1H,dd,J=7.9,1.3Hz),7.85(1H,d,J=8.1Hz),9.52(1H,s).Example 323

In the same manner as in Example 322, the following compound was obtained.
tert-butyl = 2- (2-chloroanilino) -4-phenethylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.80-2.92 (4H, m), 6.64 (1H, dd, J = 8.1, 1.6 Hz), 6.90-6.96 (2H, m), 7.08-7.30 (7H, m), 7.40 (1H, dd, J = 7.9,1.3Hz), 7.85 (1H, d, J = 8.1Hz), 9.52 (1H, s).

ベンジルブロミド41mgのＮ，Ｎ−ジメチルホルムアミド0.50mL溶液に、室温でｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート54mgおよび炭酸カリウム55mgを加え、80℃で9時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１００：１］で精製し、白色固体のｔｅｒｔ−ブチル＝２−ベンジルアミノ−４−フェニルベンゾアート45mgを得た。
¹H-NMR(CDCl₃)δ値：1.59(9H,s),4.51(2H,d,J=5.9Hz),6.78-6.83(2H,m),7.24-7.30(1H,m),7.30-7.43(7H,m),7.45-7.50(2H,m),7.91-7.96(1H,m),8.26(1H,t,J=5.9Hz).Example 324

To a solution of 41 mg of benzyl bromide in 0.50 mL of N, N-dimethylformamide was added 54 mg of tert-butyl = 2-amino-4-phenylbenzoate and 55 mg of potassium carbonate at room temperature, and the mixture was stirred at 80 ° C. for 9 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 100: 1], and white solid tert-butyl = 2-benzylamino- 45 mg of 4-phenylbenzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.59 (9H, s), 4.51 (2H, d, J = 5.9 Hz), 6.78-6.83 (2H, m), 7.24-7.30 (1H, m), 7.30- 7.43 (7H, m), 7.45-7.50 (2H, m), 7.91-7.96 (1H, m), 8.26 (1H, t, J = 5.9Hz).

４−フルオロベンジルクロリド35mgのＮ，Ｎ−ジメチルホルムアミド0.50mL溶液に、室温でｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート54mgおよび炭酸カリウム55mgを加え、80℃で11時間攪拌した。反応混合物を室温まで冷却した後、室温でヨウ化ナトリウム30mgを加え、80℃で4時間40分間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；ヘキサン：酢酸エチル＝１００：１］で精製し、白色固体のｔｅｒｔ−ブチル＝２−（４−フルオロベンジルアミノ）−４−フェニルベンゾアート26mgを得た。
¹H-NMR(CDCl₃)δ値：1.59(9H,s),4.47(2H,d,J=5.6Hz),6.77(1H,d,J=1.5Hz),6.82(1H,dd,J=8.3,1.6Hz),6.98-7.08(2H,m),7.32-7.44(5H,m),7.44-7.52(2H,m),7.94(1H,d,J=8.3Hz),8.25(1H,t,J=5.6Hz).Example 325

To a solution of 35 mg of 4-fluorobenzyl chloride in 0.50 mL of N, N-dimethylformamide was added 54 mg of tert-butyl = 2-amino-4-phenylbenzoate and 55 mg of potassium carbonate at room temperature, and the mixture was stirred at 80 ° C. for 11 hours. The reaction mixture was cooled to room temperature, 30 mg of sodium iodide was added at room temperature, and the mixture was stirred at 80 ° C. for 4 hours and 40 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent; hexane: ethyl acetate = 100: 1], and white solid tert-butyl = 2- (4- 26 mg of fluorobenzylamino) -4-phenylbenzoate was obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.59 (9H, s), 4.47 (2H, d, J = 5.6 Hz), 6.77 (1H, d, J = 1.5 Hz), 6.82 (1H, dd, J = 8.3, 1.6Hz), 6.98-7.08 (2H, m), 7.32-7.44 (5H, m), 7.44-7.52 (2H, m), 7.94 (1H, d, J = 8.3Hz), 8.25 (1H, t , J = 5.6Hz).

実施例３２５と同様にして、以下の化合物を得た。
ｔｅｒｔ−ブチル＝２−（シンナミルアミノ）−４−フェニルベンゾアート
¹H-NMR(CDCl₃)δ値：1.60(9H,s),4.07-4.13(2H,m),6.35(1H,dt,J=15.9,5.6Hz),6.67(1H,d,J=15.9Hz),6.81(1H,dd,J=8.3,1.7Hz),6.91(1H,d,J=1.7Hz),7.18-7.45(8H,m),7.54-7.60(2H,m),7.94(1H,d,J=8.3Hz),8.02-8.08(1H,m).Example 326

In the same manner as in Example 325, the following compound was obtained.
tert-Butyl = 2- (cinnamylamino) -4-phenylbenzoate
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 4.07-4.13 (2H, m), 6.35 (1H, dt, J = 15.9, 5.6Hz), 6.67 (1H, d, J = 15.9 Hz), 6.81 (1H, dd, J = 8.3,1.7Hz), 6.91 (1H, d, J = 1.7Hz), 7.18-7.45 (8H, m), 7.54-7.60 (2H, m), 7.94 (1H , d, J = 8.3Hz), 8.02-8.08 (1H, m).

２−ヨード−４−フェネチル安息香酸40mgに、室温で５−アミノインダゾール23mg、ヨウ化銅（I）2.2mg、プロリン2.6mg、炭酸カリウム19mgおよびおよびジメチルスルホキシド0.40mLを加え、70℃で3時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、水および飽和塩化ナトリウム水溶液順次洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；クロロホルム：メタノール＝１００：１］で精製し、白色固体の２−（（１Ｈ−インダゾール−５−イル）アミノ）−４−フェネチル安息香酸4.0mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.70-2.84(4H,m),6.61(1H,dd,J=8.3,1.4Hz),6.72(1H,d,J=1.4Hz),7.08-7.28(6H,m),7.46(1H,d,J=1.7Hz),7.52(1H,d,J=8.8Hz),7.80(1H,d,J=8.3Hz),8.01(1H,s),9.56(1H,s),12.70-13.20(2H,broad).Example 327

To 40 mg of 2-iodo-4-phenethylbenzoic acid, 23 mg of 5-aminoindazole, 2.2 mg of copper (I) iodide, 2.6 mg of proline, 19 mg of potassium carbonate and 0.40 mL of dimethyl sulfoxide were added at room temperature, and 3 hours at 70 ° C. Stir. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform: methanol = 100: 1] to give 2-((1H-indazole-5-5) as a white solid. Yl) amino) -4-phenethylbenzoic acid 4.0 mg was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.70-2.84 (4H, m), 6.61 (1H, dd, J = 8.3, 1.4 Hz), 6.72 (1H, d, J = 1.4 Hz), 7.08- 7.28 (6H, m), 7.46 (1H, d, J = 1.7Hz), 7.52 (1H, d, J = 8.8Hz), 7.80 (1H, d, J = 8.3Hz), 8.01 (1H, s), 9.56 (1H, s), 12.70-13.20 (2H, broad).

Examples 328-334
In the same manner as in Example 327, the compounds shown in Table 42 were obtained.

4-Phenethyl-2-((1-phenyl-1H-pyrazol-5-yl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.74.2.88 (4H, m), 6.24 (1H, d, J = 1.7 Hz), 6.69 (1H, dd, J = 8.1, 1.2 Hz), 6.80 ( 1H, d, J = 1.2Hz), 7.14-7.22 (3H, m), 7.22-7.28 (2H, m), 7.35-7.42 (1H, m), 7.44-7.55 (4H, m), 7.68 (1H, d, J = 2.0Hz), 7.76 (1H, d, J = 8.1Hz), 9.89 (1H, s), 13.07 (1H, s).

4-Phenethyl-2-((3-phenyl-1H-pyrazol-5-yl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80-2.95 (4H, m), 6.47 (1H, s), 6.68 (1H, dd, J = 8.3, 1.2 Hz), 7.14-7.20 (1H, m ), 7.20-7.31 (4H, m), 7.32-7.40 (1H, m), 7.43-7.50 (2H, m), 7.74-7.85 (4H, m), 10.15 (1H, s), 12.70-13.20 (2H) , broad).

2-((Benzothiazol-6-yl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.90 (4H, m), 6.73 (1H, dd, J = 8.2, 1.4 Hz), 7.01 (1H, s), 7.14-7.30 (6H, m ), 7.81-7.87 (2H, m), 7.98 (1H, d, J = 8.5Hz), 9.25 (1H, s), 9.78 (1H, s), 12.85-13.10 (1H, broad).

2-((1H-Indol-5-yl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.66-2.82 (4H, m), 6.37-6.42 (1H, m), 6.52-6.58 (1H, m), 6.70 (1H, s), 6.85 (1H , dd, J = 8.4,2.0Hz), 7.10-7.32 (6H, m), 7.34-7.40 (2H, m), 7.77 (1H, d, J = 8.4Hz), 9.49 (1H, s), 11.10 ( 1H, s), 12.70 (1H, s).

4-Phenethyl-2-((4-phenylthiazol-2-yl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 3.01 (4H, s), 6.95 (1H, dd, J = 8.1, 1.5 Hz), 7.14-7.22 (1H, m), 7.25-7.38 (5H, m ), 7.42-7.48 (2H, m), 7.54 (1H, s), 7.92 (1H, d, J = 8.1Hz), 7.94-7.99 (2H, m), 8.54 (1H, s), 11.40-11.50 ( 1H, broad), 13.40-13.60 (1H, broad).

4-Phenethyl-2-((5-phenyl-1,3,4-thiadiazol-2-yl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.90-3.04 (4H, m), 7.00 (1H, dd, J = 8.1,1.5Hz), 7.14-7.22 (1H, m), 7.24-7.32 (4H , m), 7.50-7.60 (3H, m), 7.86-7.96 (3H, m), 8.20 (1H, s), 11.50 (1H, s), 13.50-13.70 (1H, broad).

4-Phenethyl-2-((3-phenylisoxazol-5-yl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.90-3.06 (4H, m), 6.49-6.52 (1H, m), 6.96 (1H, dd, J = 8.1, 1.2 Hz), 7.14-7.20 (1H , m), 7.22-7.32 (4H, m), 7.37 (1H, s), 7.50-7.58 (3H, m), 7.88-7.95 (3H, m), 11.05-11.25 (1H, broad), 13.40-13.70 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート59mgのトルエン1.0mL溶液に、室温で２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.5mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mg、酢酸パラジウム0.90mg炭酸セシウム0.13gおよび３−ブロモベンズアミド0.10gを加え、4時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［富士シリシア化学株式会社、ＰＳＱ１００Ｂ（球状）、溶離液；クロロホルム：メタノール＝１００：１］で精製し、黄色固体のｔｅｒｔ−ブチル＝２−（（ベンズアミド−３−イル）アミノ）−４−フェネチルベンゾアート15mgを得た。
¹H-NMR(CDCl₃)δ値：1.60(9H,s),2.80-2.92(4H,m),5.42-5.78(1H,broad),5.78-6.18(1H,broad),6.62(1H,dd,J=8.3,1.3Hz),7.00(1H,d,J=1.3Hz),7.10-7.30(6H,m),7.34(1H,t,J=7.8Hz),7.42-7.46(1H,m),7.60(1H,t,J=1.8Hz),7.84(1H,d,J=8.3Hz),9.64(1H,s).Example 335

tert-Butyl-2-amino-4-phenethylbenzoate 59 mg in toluene 1.0 mL solution at room temperature 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 9.5 mg, tris (dibenzylideneacetone) 3.7 mg of dipalladium (0), 0.90 mg of palladium acetate, 0.13 g of cesium carbonate and 0.10 g of 3-bromobenzamide were added, and the mixture was heated to reflux for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform: methanol = 100: 1], and tert-butyl = 2-((benzamide- 15 mg of 3-yl) amino) -4-phenethylbenzoate were obtained.
¹ H-NMR (CDCl ₃ ) δ value: 1.60 (9H, s), 2.80-2.92 (4H, m), 5.42-5.78 (1H, broad), 5.78-6.18 (1H, broad), 6.62 (1H, dd , J = 8.3,1.3Hz), 7.00 (1H, d, J = 1.3Hz), 7.10-7.30 (6H, m), 7.34 (1H, t, J = 7.8Hz), 7.42-7.46 (1H, m) , 7.60 (1H, t, J = 1.8Hz), 7.84 (1H, d, J = 8.3Hz), 9.64 (1H, s).

ｔｅｒｔ−ブチル＝２−（（ビフェニル−４−イル）アミノ）−４−フェニルベンゾアート84mgの塩化メチレン2.5mL溶液に、トリフルオロ酢酸2.5mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（（ビフェニル−４−イル）アミノ）−４−フェニル安息香酸52mgを得た。
¹H-NMR(DMSO-d₆)δ値：7.11(1H,dd,J=8.3,1.7Hz),7.31-7.36(1H,m),7.37-7.56(8H,m),7.60-7.74(6H,m),8.01(1H,d,J=8.3 Hz),9.79(1H,s),13.05-13.30(1H,broad).Example 336

To a solution of 84 mg of tert-butyl = 2-((biphenyl-4-yl) amino) -4-phenylbenzoate in 2.5 mL of methylene chloride was added 2.5 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 52 mg of 2-((biphenyl-4-yl) amino) -4-phenylbenzoic acid as a yellow solid was collected. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 7.11 (1H, dd, J = 8.3,1.7Hz), 7.31-7.36 (1H, m), 7.37-7.56 (8H, m), 7.60-7.74 (6H , m), 8.01 (1H, d, J = 8.3 Hz), 9.79 (1H, s), 13.05-13.30 (1H, broad).

Examples 337-350
In the same manner as in Example 336, the compounds shown in Table 43 were obtained.

2-((biphenyl-3-yl) amino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.10 (1H, dd, J = 8.3, 1.7 Hz), 7.36-7.43 (4H, m), 7.43-7.53 (6H, m), 7.54-7.57 (1H , m), 7.58-7.64 (2H, m), 7.66-7.72 (2H, m), 8.01 (1H, d, J = 8.3 Hz), 9.79 (1H, s), 13.00-13.30 (1H, broad).

2-((Biphenyl-2-yl) amino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.99 (1H, dd, J = 8.2, 1.7 Hz), 7.22-7.49 (12H, m), 7.52-7.62 (3H, m), 7.89 (1H, d , J = 8.2Hz), 9.54 (1H, s), 12.80-13.05 (1H, broad).

2-((Isoquinolin-4-yl) amino) -4-phenylbenzoic acid trifluoroacetate
¹ H-NMR (DMSO-d ₆ ) δ value: 7.24 (1H, dd, J = 8.3, 1.7 Hz), 7.32-7.46 (4H, m), 7.53-7.59 (2H, m), 7.88-7.94 (1H , m), 8.00-8.06 (1H, m), 8.08 (1H, d, J = 8.3Hz), 8.18 (1H, d, J = 8.3Hz), 8.38 (1H, d, J = 8.3Hz), 8.68 -8.72 (1H, m), 9.34 (1H, s), 10.22 (1H, s).

4-Phenyl-2-((quinolin-8-yl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.23 (1H, dd, J = 8.3, 1.5 Hz), 7.40-7.46 (1H, m), 7.46-7.64 (5H, m), 7.69-7.74 (2H , m), 7.89 (1H, dd, J = 7.6, 1.2Hz), 7.96 (1H, d, J = 1.4Hz), 8.08 (1H, d, J = 8.3Hz), 8.38 (1H, dd, J = (8.4, 1.6Hz), 8.92 (1H, dd, J = 4.2, 1.7Hz), 11.02 (1H, s), 13.00-13.25 (1H, broad).

2- (4-Hydroxyphenylamino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.78-6.84 (2H, m), 6.94 (1H, dd, J = 8.3,1.6Hz), 7.06 (1H, d, J = 1.6Hz), 7.10- 7.16 (2H, m), 7.34-7.40 (1H, m), 7.40-7.47 (2H, m), 7.48-7.54 (2H, m), 7.93 (1H, d, J = 8.3Hz), 9.20-9.50 ( 2H, broad), 12.80-13.10 (1H, broad).

2- (2-Fluoroanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.12 (1H, dd, J = 8.3,1.7Hz), 7.13-7.20 (1H, m), 7.20-7.29 (2H, m), 7.30-7.50 (4H , m), 7.56-7.66 (3H, m), 8.01 (1H, d, J = 8.3Hz), 9.73 (1H, s), 13.10-13.40 (1H, broad).

2- (2-Chloroanilino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 7.11 (1H, td, J = 7.7, 1.5 Hz), 7.16 (1H, dd, J = 8.3, 1.7 Hz), 7.34-7.44 (3H, m), 7.44-7.50 (2H, m), 7.57 (1H, dd, J = 8.1,1.5Hz), 7.59-7.65 (2H, m), 7.65-7.70 (1H, m), 8.02 (1H, d, J = 8.3 Hz), 9.91 (1H, s), 13.10-13.40 (1H, broad).

4-Phenyl-2-((quinolin-3-yl) amino) benzoic acid trifluoroacetate
¹ H-NMR (DMSO-d ₆ ) δ value: 7.21 (1H, dd, J = 8.3,1.7 Hz), 7.36-7.43 (1H, m), 7.43-7.49 (2H, m), 7.56-7.63 (2H , m), 7.63-7.70 (3H, m), 7.96-8.02 (2H, m), 8.05 (1H, d, J = 8.3Hz), 8.35 (1H, d, J = 2.4Hz), 8.98 (1H, d, J = 2.7Hz), 9.96 (1H, s), 13.20-13.50 (1H, broad).

2-((Isoquinolin-5-yl) amino) -4-phenylbenzoic acid trifluoroacetate
¹ H-NMR (DMSO-d ₆ ) δ value: 7.16 (1H, dd, J = 8.3, 1.7 Hz), 7.23-7.28 (1H, m), 7.34-7.46 (3H, m), 7.50-7.56 (2H , m), 7.82 (1H, t, J = 7.9Hz), 8.01-8.10 (4H, m), 8.61 (1H, d, J = 6.1Hz), 9.56 (1H, s), 10.23 (1H, s) , 13.20-13.50 (1H, broad).

2- (2-hydroxyphenylamino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.80-6.88 (1H, m), 6.90-6.96 (2H, m), 7.01 (1H, dd, J = 8.3,1.7Hz), 7.30 (1H, d , J = 1.7Hz), 7.36-7.49 (4H, m), 7.54-7.60 (2H, m), 7.96 (1H, d, J = 8.3Hz), 9.53 (1H, s), 9.71 (1H, s) , 12.80-13.10 (1H, broad).

4-Phenyl-2- (3- (1H-pyrazol-1-yl) phenylamino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 6.53-6.57 (1H, m), 7.15 (1H, dd, J = 8.3,1.5Hz), 7.26-7.32 (1H, m), 7.36-7.58 (6H , m), 7.62-7.67 (2H, m), 7.75 (1H, d, J = 1.7Hz), 7.84 (1H, t, J = 2.0Hz), 8.02 (1H, d, J = 8.3Hz), 8.55 (1H, d, J = 2.7Hz), 9.81 (1H, s), 13.10-13.40 (1H, broad).

2- (Benzylamino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 4.57 (2H, s), 6.85 (1H, dd, J = 8.3, 1.6 Hz), 6.88-6.92 (1H, m), 7.22-7.29 (1H, m ), 7.32-7.48 (7H, m), 7.55-7.60 (2H, m), 7.88 (1H, d, J = 8.3Hz).

2- (4-Fluorobenzylamino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 4.56 (2H, s), 6.84-6.90 (2H, m), 7.14-7.22 (2H, m), 7.35-7.48 (5H, m), 7.55-7.60 (2H, m), 7.88 (1H, d, J = 8.3Hz).

2- (cinnamylamino) -4-phenylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 4.16 (2H, d, J = 5.5 Hz), 6.44 (1 H, dt, J = 16.0, 5.5 Hz), 6.67 (1 H, d, J = 16.0 Hz) , 6.87 (1H, dd, J = 8.3,1.6Hz), 7.00 (1H, d, J = 1.6Hz), 7.20-7.26 (1H, m), 7.29-7.50 (7H, m), 7.65-7.70 (2H , m), 7.88 (1H, d, J = 8.3Hz).

ｔｅｒｔ−ブチル＝２−（（ビフェニル−４−イル）アミノ）−４−フェネチルベンゾアート50mgの塩化メチレン2.0mL溶液に、トリフルオロ酢酸2.0mLを加え、室温で4時間30分間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（（ビフェニル−４−イル）アミノ）−４−フェネチル安息香酸27mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.80-2.92(4H,m),6.72(1H,d,J=8.6Hz),7.05(1H,s),7.12-7.25(5H,m),7.25-7.38(3H,m),7.46(2H,t,J=7.7Hz),7.61(2H,d,J=8.6Hz),7.66(2H,d,J=7.3Hz),7.83(1H,d,J=8.3Hz),9.68(1H,s),12.80-13.15(1H,broad).Example 351

To a 2.0 mL methylene chloride solution of 50 mg of tert-butyl = 2-((biphenyl-4-yl) amino) -4-phenethylbenzoate was added 2.0 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 4 hours and 30 minutes. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the obtained residue, the solid was collected by filtration, and 27 mg of 2-((biphenyl-4-yl) amino) -4-phenethylbenzoic acid as a yellow solid was collected. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80-2.92 (4H, m), 6.72 (1H, d, J = 8.6 Hz), 7.05 (1H, s), 7.12-7.25 (5H, m), 7.25-7.38 (3H, m), 7.46 (2H, t, J = 7.7Hz), 7.61 (2H, d, J = 8.6Hz), 7.66 (2H, d, J = 7.3Hz), 7.83 (1H, d , J = 8.3Hz), 9.68 (1H, s), 12.80-13.15 (1H, broad).

Examples 352-364
In the same manner as in Example 351, the compounds shown in Table 44 were obtained.

2-((biphenyl-3-yl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.90 (4H, m), 6.71 (1H, dd, J = 8.2, 1.2 Hz), 7.04-7.11 (2H, m), 7.13-7.20 (3H , m), 7.21-7.28 (2H, m), 7.30-7.50 (6H, m), 7.64-7.70 (2H, m), 7.82 (1H, d, J = 8.2Hz), 9.67 (1H, s), 12.80-13.10 (1H, broad).

2-((biphenyl-2-yl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.74-2.88 (4H, m), 6.61 (1H, dd, J = 8.1, 1.5Hz), 6.81-6.85 (1H, m), 7.12-7.23 (5H , m), 7.23-7.42 (9H, m), 7.72 (1H, d, J = 8.1Hz), 9.42 (1H, s), 12.60-12.80 (1H, broad).

2-((Isoquinolin-4-yl) amino) -4-phenethylbenzoic acid trifluoroacetate
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80 (4H, s), 6.81 (1H, d, J = 7.3 Hz), 6.98 (1H, s), 7.10-7.16 (3H, m), 7.18- 7.26 (2H, m), 7.84-7.92 (2H, m), 7.96-8.02 (1H, m), 8.08-8.14 (1H, m), 8.34 (1H, d, J = 8.3Hz), 8.48 (1H, s), 9.28 (1H, s), 10.12 (1H, s), 13.10-13.30 (1H, broad).

4-phenethyl-2-((quinolin-8-yl) amino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.93 (4H, s), 6.83 (1H, dd, J = 8.2, 1.2 Hz), 7.18-7.26 (3H, m), 7.27-7.38 (3H, m ), 7.41-7.48 (3H, m), 7.59 (1H, dd, J = 8.3, 4.2Hz), 7.89 (1H, d, J = 8.2Hz), 8.34 (1H, dd, J = 8.2, 1.6Hz) , 8.88 (1H, dd, J = 4.2,1.7Hz), 10.90 (1H, s), 12.91 (1H, s).

2- (4-Hydroxyphenylamino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.72-2.84 (4H, m), 6.56 (1H, dd, J = 8.2, 1.5 Hz), 6.63 (1H, s), 6.71-6.77 (2H, m ), 6.86-6.92 (2H, m), 7.12-7.28 (5H, m), 7.75 (1H, d, J = 8.2Hz), 9.32 (2H, s), 12.60-12.90 (1H, broad).

2- (2-Fluoroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.85 (4H, s), 6.74 (1H, dd, J = 8.1, 1.5 Hz), 6.87 (1H, s), 7.04-7.32 (9H, m), 7.83 (1H, d, J = 8.1Hz), 9.63 (1H, s), 12.90-13.20 (1H, broad).

2- (2-Chloroanilino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.86 (4H, s), 6.78 (1H, dd, J = 8.2, 1.3 Hz), 6.94 (1H, d, J = 1.3 Hz), 7.01-7.06 ( 1H, m), 7.15-7.30 (7H, m), 7.51 (1H, dd, J = 8.0,1.5Hz), 7.85 (1H, d, J = 8.2Hz), 9.80 (1H, s), 12.90-13.20 (1H, broad).

4-phenethyl-2-((quinolin-3-yl) amino) benzoic acid trifluoroacetate
¹ H-NMR (DMSO-d ₆ ) δ value: 2.88 (4H, s), 6.82 (1H, dd, J = 8.2, 1.5 Hz), 7.12-7.28 (6H, m), 7.58-7.70 (2H, m ), 7.88 (1H, d, J = 8.2Hz), 7.92 (1H, dd, J = 7.9, 1.4Hz), 7.99 (1H, d, J = 7.8Hz), 8.14 (1H, d, J = 2.4Hz) ), 8.87 (1H, d, J = 2.7Hz), 9.90 (1H, s), 13.00-13.20 (1H, broad).

2-((Isoquinolin-5-yl) amino) -4-phenethylbenzoic acid trifluoroacetate
¹ H-NMR (DMSO-d ₆ ) δ value: 2.81 (4H, s), 6.79 (1H, dd, J = 8.1, 1.5 Hz), 6.84 to 6.88 (1H, m), 7.10-7.27 (5H, m ), 7.63 (1H, d, J = 7.6Hz), 7.74 (1H, t, J = 7.9Hz), 7.90 (1H, d, J = 8.1Hz), 7.98-8.04 (2H, m), 8.59 (1H , d, J = 6.1 Hz), 9.56 (1H, s), 10.16 (1H, s), 13.00-13.30 (1H, broad).

2- (2-Hydroxyphenylamino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.76-2.90 (4H, m), 6.63 (1H, dd, J = 8.1,1.3Hz), 6.70-6.76 (1H, m), 6.82-6.95 (3H , m), 7.02 (1H, dd, J = 7.8,1.0Hz), 7.14-7.23 (3H, m), 7.23-7.30 (2H, m), 7.79 (1H, d, J = 8.1Hz), 9.44 ( 1H, s), 9.63 (1H, s), 12.73 (1H, s).

4-Phenethyl-2- (3- (1H-pyrazol-1-yl) phenylamino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80-2.92 (4H, m), 6.52-6.56 (1H, m), 6.74 (1H, dd, J = 8.0,1.5Hz), 6.98 (1H, dd , J = 7.9,1.3Hz), 7.12 (1H, d, J = 1.2Hz), 7.14-7.30 (5H, m), 7.39 (1H, t, J = 8.1Hz), 7.47-7.52 (1H, m) , 7.68 (1H, t, J = 2.1Hz), 7.73 (1H, d, J = 1.7Hz), 7.84 (1H, d, J = 8.0Hz), 8.51 (1H, d, J = 2.4Hz), 9.70 (1H, s), 13.01 (1H, s).

4-Phenethyl-2- (4- (1H-pyrazol-1-yl) phenylamino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80-2.90 (4H, m), 6.53 (1H, dd, J = 2.4,2.0Hz), 6.71 (1H, dd, J = 8.3,1.5Hz), 6.96 (1H, d, J = 1.5Hz), 7.14-7.31 (7H, m), 7.72-7.78 (3H, m), 7.83 (1H, d, J = 8.3Hz), 8.45 (1H, d, J = 2.4Hz), 9.64 (1H, s), 12.96 (1H, s).

2-((Benzamido-3-yl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.80-2.90 (4H, m), 6.71 (1H, d, J = 8.0 Hz), 7.03 (1H, s), 7.14-7.30 (6H, m), 7.34-7.40 (2H, m), 7.53 (1H, d, J = 7.3Hz), 7.67 (1H, s), 7.82 (1H, d, J = 8.0Hz), 7.97 (1H, s), 9.68 (1H , s), 12.99 (1H, s).

ｔｅｒｔ−ブチル＝４−フェネチル−２−（３−（１Ｈ−ピロール−１−イル）フェニルアミノ）ベンゾアート83mgのジオキサン2.0mL溶液に、メタノール2.0mLおよび2.0mol/L水酸化ナトリウム水溶液1.0mLを加え、3時間加熱還流した。反応混合物を室温まで冷却した後、酢酸エチルおよび1.0mol/L塩酸を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の４−フェネチル−２−（３−（１Ｈ−ピロール−１−イル）フェニルアミノ）安息香酸36mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.86(4H,s),6.23-6.28(2H,m),6.73(1H,dd,J=8.3,1.2Hz),6.90-6.94(1H,m),7.09(1H,s),7.14-7.28(6H,m),7.32-7.40(4H,m),7.83(1H,d,J=8.3Hz),9.65(1H,s),12.85-13.10(1H,broad).Example 365

tert-Butyl 4-phenethyl-2- (3- (1H-pyrrol-1-yl) phenylamino) benzoate 83 mg in dioxane 2.0 mL is mixed with 2.0 mL methanol and 1.0 mL 2.0 mol / L sodium hydroxide aqueous solution. In addition, the mixture was heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol / L hydrochloric acid were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 36 mg of white solid 4-phenethyl-2- (3- (1H-pyrrol-1-yl) phenylamino) benzoic acid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.86 (4H, s), 6.23-6.28 (2H, m), 6.73 (1H, dd, J = 8.3, 1.2 Hz), 6.90-6.94 (1H, m ), 7.09 (1H, s), 7.14-7.28 (6H, m), 7.32-7.40 (4H, m), 7.83 (1H, d, J = 8.3Hz), 9.65 (1H, s), 12.85-13.10 ( 1H, broad).

実施例３６５と同様にして、以下の化合物を得た。
４−フェネチル−２−（４−（１Ｈ−ピロール−１−イル）フェニルアミノ）安息香酸
¹H-NMR(DMSO-d₆)δ値：2.78-2.90(4H,m),6.26(2H,t,J=2.2Hz),6.69(1H,dd,J=8.2,1.2Hz),6.94(1H,s),7.12-7.24(5H,m),7.24-7.31(2H,m),7.33(2H,t,J=2.2Hz),7.46-7.52(2H,m),7.82(1H,d,J=8.2),9.60(1H,s),12.92(1H,s).Example 366

In the same manner as in Example 365, the following compound was obtained.
4-Phenethyl-2- (4- (1H-pyrrol-1-yl) phenylamino) benzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.78-2.90 (4H, m), 6.26 (2H, t, J = 2.2Hz), 6.69 (1H, dd, J = 8.2, 1.2Hz), 6.94 ( 1H, s), 7.12-7.24 (5H, m), 7.24-7.31 (2H, m), 7.33 (2H, t, J = 2.2Hz), 7.46-7.52 (2H, m), 7.82 (1H, d, J = 8.2), 9.60 (1H, s), 12.92 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.12gの２−メチル−２−プロパノール2.5mL溶液に、室温で炭酸セシウム0.26g、Ｎ−（３−ブロモフェニル）アセトアミド0.13g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル10mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mgおよび酢酸パラジウム2.0mgを加え、80℃で4時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mg、酢酸パラジウム2.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル10mgを加え、80℃で12時間攪拌した。炭酸セシウム0.26g、Ｎ−（３−ブロモフェニル）アセトアミド0.13g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル10mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mgおよび酢酸パラジウム2.0mgを加え、80℃で5時間30分間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、ｔｅｒｔ−ブチル＝２−（（３−（アセトアミド）フェニル）アミノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（３−（アセトアミド）フェニル）アミノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸7.5mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、白色固体の２−（（３−（アセトアミド）フェニル）アミノ）−４−フェネチル安息香酸0.12gを得た。
¹H-NMR(DMSO-d₆)δ値：2.04(3H,s),2.78-2.90(4H,m),6.68(1H,d,J=8.2Hz),6.73(1H,d,J=7.8Hz),7.10-7.29(8H,m),7.62(1H,s),7.81(1H,d,J=8.2Hz),9.64(1H,s),9.92(1H,s),12.95(1H,s).Example 367

tert-Butyl-2-amino-4-phenethylbenzoate 0.12 g in 2-methyl-2-propanol 2.5 mL solution at room temperature 0.26 g cesium carbonate, 0.13 g N- (3-bromophenyl) acetamide, 2-dicyclohexyl Phosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 10 mg, tris (dibenzylideneacetone) dipalladium (0) 4.0 mg and palladium acetate 2.0 mg were added, and the mixture was stirred at 80 ° C. for 4 hours. Tris (dibenzylideneacetone) dipalladium (0) 4.0 mg, palladium acetate 2.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 10 mg were added, and the mixture was stirred at 80 ° C. for 12 hours. Cesium carbonate 0.26 g, N- (3-bromophenyl) acetamide 0.13 g, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 10 mg, tris (dibenzylideneacetone) dipalladium (0) 4.0 mg Then, 2.0 mg of palladium acetate was added, and the mixture was stirred at 80 ° C. for 5 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 2: 1], and tert-butyl = 2 ((3- (acetamido) phenyl). Amino) -4-phenethylbenzoate was obtained.
7.5 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2-((3- (acetamido) phenyl) amino) -4-phenethylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, the solid was collected by filtration, and white solid 2-((3- (acetamido) phenyl) amino) -4-phenethylbenzoic acid 0.12 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.04 (3H, s), 2.78-2.90 (4H, m), 6.68 (1H, d, J = 8.2 Hz), 6.73 (1H, d, J = 7.8 Hz), 7.10-7.29 (8H, m), 7.62 (1H, s), 7.81 (1H, d, J = 8.2Hz), 9.64 (1H, s), 9.92 (1H, s), 12.95 (1H, s) ).

実施例３６７と同様にして、以下の化合物を得た。
２−（（３−（メタンスルホンアミド）フェニル）アミノ）−４−フェネチル安息香酸
¹H-NMR(DMSO-d₆)δ値：2.79-2.90(4H,m),3.02(3H,s),6.70(1H,d,J=8.3Hz),6.80(1H,dd,J=8.1,1.0Hz),6.87(1H,dd,J=8.1,1.0Hz),7.10-7.30(8H,m),7.82(1H,d,J=8.3Hz),9.66(1H,s),9.75(1H,s),12.80-13.20(1H,broad).Example 368

In the same manner as in Example 367, the following compound was obtained.
2-((3- (Methanesulfonamido) phenyl) amino) -4-phenethylbenzoic acid
¹ H-NMR (DMSO-d ₆ ) δ value: 2.79-2.90 (4H, m), 3.02 (3H, s), 6.70 (1H, d, J = 8.3 Hz), 6.80 (1H, dd, J = 8.1 , 1.0Hz), 6.87 (1H, dd, J = 8.1,1.0Hz), 7.10-7.30 (8H, m), 7.82 (1H, d, J = 8.3Hz), 9.66 (1H, s), 9.75 (1H , s), 12.80-13.20 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.12gの２−メチル−２−プロパノール2.5mL溶液に、室温で炭酸セシウム0.26g、Ｎ−（４−ヨードフェニル）アセトアミド0.16g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル10mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mgおよび酢酸パラジウム2.0mgを加え、80℃で4時間攪拌した。トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mg、酢酸パラジウム2.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル10mgを加え、80℃で12時間攪拌した。炭酸セシウム0.26g、Ｎ−（４−ヨードフェニル）アセトアミド0.16g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル10mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mgおよび酢酸パラジウム2.0mgを加え、80℃で5時間30分間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル10mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mgおよび酢酸パラジウム2.0mgを加え、80℃で12時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１：１］で精製し、ｔｅｒｔ−ブチル＝２−（（４−（アセトアミド）フェニル）アミノ）−４−フェネチルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（４−（アセトアミド）フェニル）アミノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸7.5mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にメタノールを加え、固形物をろ取し、白色固体の２−（（４−（アセトアミド）フェニル）アミノ）−４−フェネチル安息香酸23mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.04(3H,s),2.76-2.87(4H,m),6.64(1H,d,J=8.2Hz),6.82(1H,s),6.98(2H,d,J=8.8Hz),7.13-7.22(3H,m),7.23-7.29(2H,m),7.53(2H,d,J=8.8Hz),7.79(1H,d,J=8.2Hz),9.50(1H,s),9.90(1H,s),12.85(1H,s).Example 369

To a solution of 0.12 g of tert-butyl = 2-amino-4-phenethylbenzoate in 2.5 mL of 2-methyl-2-propanol, 0.26 g of cesium carbonate, 0.16 g of N- (4-iodophenyl) acetamide, 2-dicyclohexyl at room temperature Phosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 10 mg, tris (dibenzylideneacetone) dipalladium (0) 4.0 mg and palladium acetate 2.0 mg were added, and the mixture was stirred at 80 ° C. for 4 hours. Tris (dibenzylideneacetone) dipalladium (0) 4.0 mg, palladium acetate 2.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 10 mg were added, and the mixture was stirred at 80 ° C. for 12 hours. Cesium carbonate 0.26 g, N- (4-iodophenyl) acetamide 0.16 g, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 10 mg, tris (dibenzylideneacetone) dipalladium (0) 4.0 mg Then, 2.0 mg of palladium acetate was added, and the mixture was stirred at 80 ° C. for 5 hours and 30 minutes. 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (10 mg), tris (dibenzylideneacetone) dipalladium (0) (4.0 mg) and palladium acetate (2.0 mg) were added, and the mixture was stirred at 80 ° C. for 12 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent; hexane: ethyl acetate = 1: 1], and tert-butyl = 2-((4- (acetamido) phenyl). Amino) -4-phenethylbenzoate was obtained.
7.5 mL of trifluoroacetic acid was added to the obtained tert-butyl = 2-((4- (acetamido) phenyl) amino) -4-phenethylbenzoate, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, methanol was added to the obtained residue, the solid was collected by filtration, and 23 mg of 2-((4- (acetamido) phenyl) amino) -4-phenethylbenzoic acid as a white solid was collected. Obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.04 (3H, s), 2.76-2.87 (4H, m), 6.64 (1H, d, J = 8.2 Hz), 6.82 (1H, s), 6.98 ( 2H, d, J = 8.8Hz), 7.13-7.22 (3H, m), 7.23-7.29 (2H, m), 7.53 (2H, d, J = 8.8Hz), 7.79 (1H, d, J = 8.2Hz ), 9.50 (1H, s), 9.90 (1H, s), 12.85 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.12gの２−メチル−２−プロパノール2.5mL溶液に、室温で炭酸セシウム0.29g、Ｎ−（３−ブロモフェニル）アセトアミド0.14g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル11mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mgおよび酢酸パラジウム2.0mgを加え、80℃で4時間攪拌した。室温でトリス（ジベンジリデンアセトン）ジパラジウム（０）4.0mg、酢酸パラジウム2.0mgおよび２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル11mgを加え、80℃で12時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび水を加えた。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝２：１］で精製し、ｔｅｒｔ−ブチル＝２−（（３−（アセトアミド）フェニル）アミノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（３−（アセトアミド）フェニル）アミノ）−４−フェニルベンゾアートに、トリフルオロ酢酸7.5mLを加え、室温で2時間攪拌した。減圧下で溶媒を留去し、得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、黄色固体の２−（（３−（アセトアミド）フェニル）アミノ）−４−フェニル安息香酸0.13gを得た。
¹H-NMR(DMSO-d₆)δ値：2.05(3H,s),6.96(1H,dd,J=8.1,1.2Hz),7.09(1H,dd,J=8.3,1.7Hz),7.16-7.31(2H,m),7.37-7.49(3H,m),7.52(1H,d,J=1.7Hz),7.63-7.69(2H,m),7.78(1H,s),8.00(1H,d,J=8.3Hz),9.75(1H,s),9.98(1H,s),13.15(1H,s).Example 370

To a solution of 0.12 g of tert-butyl = 2-amino-4-phenylbenzoate in 2.5 mL of 2-methyl-2-propanol, 0.29 g of cesium carbonate, 0.14 g of N- (3-bromophenyl) acetamide, 2-dicyclohexyl at room temperature Phosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (11 mg), tris (dibenzylideneacetone) dipalladium (0) (4.0 mg) and palladium acetate (2.0 mg) were added, and the mixture was stirred at 80 ° C. for 4 hours. At room temperature, tris (dibenzylideneacetone) dipalladium (0) 4.0 mg, palladium acetate 2.0 mg and 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 11 mg were added, and the mixture was stirred at 80 ° C. for 12 hours. . After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 2: 1], and tert-butyl = 2 ((3- (acetamido) phenyl). Amino) -4-phenylbenzoate was obtained.
To the obtained tert-butyl = 2-((3- (acetamido) phenyl) amino) -4-phenylbenzoate, 7.5 mL of trifluoroacetic acid was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, diisopropyl ether was added to the resulting residue, the solid was collected by filtration, and yellow solid 2-((3- (acetamido) phenyl) amino) -4-phenylbenzoic acid 0.13 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.05 (3H, s), 6.96 (1H, dd, J = 8.1, 1.2 Hz), 7.09 (1H, dd, J = 8.3, 1.7 Hz), 7.16- 7.31 (2H, m), 7.37-7.49 (3H, m), 7.52 (1H, d, J = 1.7Hz), 7.63-7.69 (2H, m), 7.78 (1H, s), 8.00 (1H, d, J = 8.3Hz), 9.75 (1H, s), 9.98 (1H, s), 13.15 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.12gおよび炭酸セシウム0.36gのトルエン3.0mL懸濁液に、室温で４−ブロモ−Ｎ，Ｎ−ジメチルアニリン0.18g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル11mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.1mgおよび酢酸パラジウム2.0mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル11mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.1mgおよび酢酸パラジウム2.0mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（４−（ジメチルアミノ）フェニル）アミノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（４−（ジメチルアミノ）フェニル）アミノ）−４−フェニルベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.5に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物に酢酸エチルを加え、固形物をろ取し、黄色固体の２−（（４−（ジメチルアミノ）フェニル）アミノ）−４−フェニル安息香酸61mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.90(6H,s),6.75-6.81(2H,m),6.92(1H,dd,J=8.3,1.6Hz),7.07(1H,d,J=1.6Hz),7.12-7.18(2H,m),7.34-7.53(5H,m),7.93(1H,d,J=8.3Hz),9.35-9.50(1H,broad),12.80-13.05(1H,broad).Example 371

A suspension of 0.12 g of tert-butyl = 2-amino-4-phenylbenzoate and 0.36 g of cesium carbonate in 3.0 mL of toluene was added at room temperature to 0.18 g of 4-bromo-N, N-dimethylaniline, 2-dicyclohexylphosphino- 2 mg of 2 ′, 4 ′, 6′-triisopropylbiphenyl, 4.1 mg of tris (dibenzylideneacetone) dipalladium (0) and 2.0 mg of palladium acetate were added and stirred at 110 ° C. for 24 hours. 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (11 mg), tris (dibenzylideneacetone) dipalladium (0) (4.1 mg) and palladium acetate (2.0 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((4- (dimethylamino) phenyl ) Amino) -4-phenylbenzoate was obtained.
To the obtained tert-butyl = 2-((4- (dimethylamino) phenyl) amino) -4-phenylbenzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the resulting residue, and the pH was adjusted to 6.5 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the solid was collected by filtration to obtain 61 mg of 2-((4- (dimethylamino) phenyl) amino) -4-phenylbenzoic acid as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.90 (6H, s), 6.75-6.81 (2H, m), 6.92 (1H, dd, J = 8.3, 1.6 Hz), 7.07 (1H, d, J = 1.6Hz), 7.12-7.18 (2H, m), 7.34-7.53 (5H, m), 7.93 (1H, d, J = 8.3Hz), 9.35-9.50 (1H, broad), 12.80-13.05 (1H, broad).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェニルベンゾアート0.12gおよび炭酸セシウム0.36gのトルエン3.0mL懸濁液に、室温で２−ブロモ−Ｎ，Ｎ−ジメチルアニリン0.18g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル11mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.1mgおよび酢酸パラジウム2.0mgを加え、110℃で24時間攪拌した。２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル11mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.1mgおよび酢酸パラジウム2.0mgを加え、110℃で21時間攪拌した。炭酸セシウム73mg、２−ブロモ−Ｎ，Ｎ−ジメチルアニリン45mg、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル11mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）4.1mgおよび酢酸パラジウム2.0mgを加え、110℃で24時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（２−（ジメチルアミノ）フェニル）アミノ）−４−フェニルベンゾアートを得た。
得られたｔｅｒｔ−ブチル＝２−（（２−（ジメチルアミノ）フェニル）アミノ）−４−フェニルベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物を逆相シリカゲルカラムクロマトグラフィー［溶離液；50-85％アセトニトリル/0.1％トリフルオロ酢酸水溶液］で精製後、酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.5に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にヘキサンを加え、固形物をろ取し、黄色固体の２−（（２−（ジメチルアミノ）フェニル）アミノ）−４−フェニル安息香酸17mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.65(6H,s),7.00-7.08(3H,m),7.10-7.16(1H,m),7.36-7.50(5H,m),7.57-7.62(2H,m),7.98(1H,d,J=8.3Hz),9.67(1H,s),12.95(1H,s).Example 372

To a suspension of 0.12 g of tert-butyl = 2-amino-4-phenylbenzoate and 0.36 g of cesium carbonate in 3.0 mL of toluene was added 0.18 g of 2-bromo-N, N-dimethylaniline at room temperature, 2-dicyclohexylphosphino- 2 mg of 2 ′, 4 ′, 6′-triisopropylbiphenyl, 4.1 mg of tris (dibenzylideneacetone) dipalladium (0) and 2.0 mg of palladium acetate were added and stirred at 110 ° C. for 24 hours. 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (11 mg), tris (dibenzylideneacetone) dipalladium (0) (4.1 mg) and palladium acetate (2.0 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. Cesium carbonate 73 mg, 2-bromo-N, N-dimethylaniline 45 mg, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl 11 mg, tris (dibenzylideneacetone) dipalladium (0) 4.1 mg and 2.0 mg of palladium acetate was added and stirred at 110 ° C. for 24 hours. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((2- (dimethylamino) phenyl ) Amino) -4-phenylbenzoate was obtained.
To the obtained tert-butyl = 2-((2- (dimethylamino) phenyl) amino) -4-phenylbenzoate, 5.0 mL of trifluoroacetic acid was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by reverse phase silica gel column chromatography [eluent: 50-85% acetonitrile / 0.1% aqueous trifluoroacetic acid solution], and then added with ethyl acetate and water to saturate The pH was adjusted to 6.5 with an aqueous sodium bicarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue, and the solid substance was collected by filtration to obtain 17 mg of 2-((2- (dimethylamino) phenyl) amino) -4-phenylbenzoic acid as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.65 (6H, s), 7.00-7.08 (3H, m), 7.10-7.16 (1H, m), 7.36-7.50 (5H, m), 7.57-7.62 (2H, m), 7.98 (1H, d, J = 8.3Hz), 9.67 (1H, s), 12.95 (1H, s).

ｔｅｒｔ−ブチル＝２−アミノ−４−フェネチルベンゾアート0.12gおよび炭酸セシウム0.33gのトルエン3.0mL懸濁液に、室温で４−ブロモ−Ｎ，Ｎ−ジメチルアニリン0.16g、２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mgおよび酢酸パラジウム1.8mgを加え、110℃で24時間攪拌した。室温で２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピルビフェニル9.6mg、トリス（ジベンジリデンアセトン）ジパラジウム（０）3.7mgおよび酢酸パラジウム1.8mgを加え、110℃で21時間攪拌した。反応混合物を室温まで冷却した後、酢酸エチルおよび10％クエン酸水溶液を加え、不溶物をろ去した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［トリコネックス社、フラッシュチューブ２００８、溶離液；ヘキサン：酢酸エチル＝１０：１］で精製し、ｔｅｒｔ−ブチル＝２−（（４−（ジメチルアミノ）フェニル）アミノ）−４−フェネチルベンゾアートを得た。
ｔｅｒｔ−ブチル＝２−（（４−（ジメチルアミノ）フェニル）アミノ）−４−フェネチルベンゾアートに、トリフルオロ酢酸5.0mLを加え、室温で3時間攪拌した。減圧下で溶媒を留去し、得られた残留物に酢酸エチルおよび水を加え、飽和炭酸水素ナトリウム水溶液でpH6.5に調整した。有機層を分取し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥させ、減圧下で溶媒を留去した。得られた残留物にジイソプロピルエーテルを加え、固形物をろ取し、淡黄色固体の２−（（４−（ジメチルアミノ）フェニル）アミノ）−４−フェネチル安息香酸83mgを得た。
¹H-NMR(DMSO-d₆)δ値：2.70-2.85(4H,m),2.89(6H,s),6.54(1H,dd,J=8.1,1.6Hz),6.63-6.67(1H,m),6.69-6.75(2H,m),6.91-6.98(2H,m),7.12-7.31(5H,m),7.75(1H,d,J=8.1Hz).Example 373

To a suspension of 0.12 g of tert-butyl = 2-amino-4-phenethylbenzoate and 0.33 g of cesium carbonate in 3.0 mL of toluene was added 0.16 g of 4-bromo-N, N-dimethylaniline at room temperature, 2-dicyclohexylphosphino- 9.6 mg of 2 ′, 4 ′, 6′-triisopropylbiphenyl, 3.7 mg of tris (dibenzylideneacetone) dipalladium (0) and 1.8 mg of palladium acetate were added, and the mixture was stirred at 110 ° C. for 24 hours. At room temperature, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (9.6 mg), tris (dibenzylideneacetone) dipalladium (0) (3.7 mg) and palladium acetate (1.8 mg) were added, and the mixture was stirred at 110 ° C. for 21 hours. did. The reaction mixture was cooled to room temperature, ethyl acetate and 10% aqueous citric acid solution were added, and the insoluble material was removed by filtration. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [Triconex, Flashtube 2008, eluent: hexane: ethyl acetate = 10: 1], and tert-butyl = 2-((4- (dimethylamino) phenyl ) Amino) -4-phenethylbenzoate was obtained.
To tert-butyl = 2-((4- (dimethylamino) phenyl) amino) -4-phenethylbenzoate was added 5.0 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added to the resulting residue, and the pH was adjusted to 6.5 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid was collected by filtration to obtain 83 mg of 2-((4- (dimethylamino) phenyl) amino) -4-phenethylbenzoic acid as a pale yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ value: 2.70-2.85 (4H, m), 2.89 (6H, s), 6.54 (1H, dd, J = 8.1,1.6 Hz), 6.63-6.67 (1H, m ), 6.69-6.75 (2H, m), 6.91-6.98 (2H, m), 7.12-7.31 (5H, m), 7.75 (1H, d, J = 8.1Hz).

  The compound of the present invention has MMP-13 production inhibitory action and is useful as a therapeutic agent for diseases involving MMP-13 such as rheumatoid arthritis, osteoarthritis and cancer.

Claims (7)

General formula

“Wherein R ¹ represents a hydrogen atom ; R ² represents a hydrogen atom ; R ³ represents a monocyclic heterocyclic group substituted with a phenyl group; or the following substituent group (1) A phenyl, cycloalkyl or bicyclic heterocyclic group optionally substituted with one or more groups; R ⁴ represents one or more groups selected from the following substituent groups (2) and (3): A phenyl, thienyl, cycloalkyl, cycloalkenyl or bicyclic heterocyclic group optionally substituted with; or a pyridyl group optionally substituted with an alkoxy group ; X ¹ is an alkylene or alkenylene group or bond X ² is a carbonyl group or a general formula —X ³ —X ⁴ —, —X ⁴ —X ³ —, —O—X ⁴ — or —X ⁴ —C (O) NH— (where each general The bond on the left side of the formula binds to R ⁴ “In the formula, X ³ represents a sulfur atom, an imino group, a sulfonyl group or a bond; and X ⁴ represents an alkylene or alkenylene group or bond optionally substituted with a phenyl group . Is a group represented by. Or an anthranilic acid derivative or a salt thereof.
[Substituent group (1)]
Halogen atom , nitro group, acyl group , alkanesulfonamide group, acetamide group, carbamoyl group , lower alkylamino group, amino group , hydroxyl group , alkyl group optionally substituted by one or more halogen atoms , one or more An alkoxy group, an aryl group , a cyclic amino group or a heterocyclic group which may be substituted with a halogen atom of [substituent group (2)]
Alkyl , alkoxy or heterocyclic group optionally substituted with one or more groups selected from a halogen atom and a hydroxyl group [substituent group (3)]
Halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamide group, carbamoyl group, sulfamoyl group, lower alkylamino group, amino group or hydroxyl group R ³ is a monocyclic heterocyclic group substituted with a phenyl group ; or phenyl or a bicyclic heterocyclic ring optionally substituted with one or more groups selected from the following substituent group (1a) Shikimoto; R ⁴ is the following substituent group (2a) and (3a) from one or more phenyl optionally substituted or bicyclic heterocyclic group in group according to claim 1, wherein the selected Anthranilic acid derivatives or salts thereof.
[Substituent Group (1a)]
Halogen atom, hydroxyl group, one or more optionally substituted alkyl group with a halogen atom, one or more which may be an alkoxy group substituted with a halogen atom, an aryl group, cyclic amino group, or a heterocyclic group [ Substituent Group (2a)]
An alkyl , alkoxy or heterocyclic group optionally substituted with one or more groups selected from a halogen atom and a hydroxyl group [substituent group (3a)]
Halogen atom, cyano group, nitro group, acyl group, alkanesulfonyl group, alkanesulfonamide group, acetamide group, carbamoyl group, sulfamoyl group, lower alkylamino group, amino group or hydroxyl group X ² is a carbonyl group, or a general formula —O—X ^4a — or —X ^4a —C (O) NH— (where the bond on the left side of each general formula is bonded to R ⁴ ). In the formula, X ^4a means an alkylene group or a bond optionally substituted with a phenyl group . ”The anthranilic acid derivative or a salt thereof according to claim 1 or 2 . X ² is represented by the general formula -X ^3a -X ^4b -or -X ^4b -X ^3a- (provided that the bond on the left side of each general formula is bonded to R ⁴ ) "wherein X ^3a Represents a sulfur atom, an imino group or a bond; X ^4b represents an alkylene or alkenylene group or a bond. The anthranilic acid derivative or a salt thereof according to claim 1 or 2 . The anthranilic acid derivative or a salt thereof according to claim 1 or 2 , wherein X ² is an alkylene group or a bond. A matrix metalloprotease 13 production inhibitor containing the anthranilic acid derivative or a salt thereof according to any one of claims 1 to 5 . The therapeutic agent for a rheumatoid arthritis disease containing the anthranilic acid derivative or its salt as described in any one of Claims 1-5 .